Heteroaryl-ureas and their use as glucokinase activators

ABSTRACT

This invention relates to compounds of formula (I) 
                         
which are activators of glucokinase and thus may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

FIELD OF THE INVENTION

This invention relates to compounds that are activators of glucokinaseand thus may be useful for the management, treatment, control, oradjunct treatment of diseases, where increasing glucokinase activity isbeneficial.

BACKGROUND OF THE INVENTION

Diabetes is characterised by an impaired glucose metabolism manifestingitself among other things by an elevated blood glucose level in thediabetic patients. Underlying defects lead to a classification ofdiabetes into two major groups: Type 1 diabetes, or insulin demandingdiabetes mellitus (IDDM), which arises when patients lack β-cellsproducing insulin in their pancreatic glands, and type 2 diabetes, ornon-insulin dependent diabetes mellitus (NIDDM), which occurs inpatients with an impaired β-cell function besides a range of otherabnormalities.

Type 1 diabetic patients are currently treated with insulin, while themajority of type 2 diabetic patients are treated either withsulphonylureas that stimulate β-cell function or with agents thatenhance the tissue sensitivity of the patients towards insulin or withinsulin. Among the agents applied to enhance tissue sensitivity towardsinsulin, metformin is a representative example.

Even though sulphonylureas are widely used in the treatment of NIDDMthis therapy is, in most instances, not satisfactory: In a large numberof NIDDM patients sulphonylureas do not suffice to normalise blood sugarlevels and the patients are, therefore, at high risk for acquiringdiabetic complications. Also, many patients gradually lose the abilityto respond to treatment with sulphonylureas and are thus graduallyforced into insulin treatment. This shift of patients from oralhypoglycemic agents to insulin therapy is usually ascribed to exhaustionof the β-cells in NIDDM patients.

In normal subjects as well as in diabetic subjects, the liver producesglucose in order to avoid hypoglycemia. This glucose production isderived either from the release of glucose from glycogen stores or fromgluconeogenesis, which is a de novo intracellular synthesis of glucose.In type 2 diabetes, however, the regulation of hepatic glucose output ispoorly controlled and is increased, and may be doubled after anovernight fast. Moreover, in these patients there exists a strongcorrelation between the increased fasting plasma glucose levels and therate of hepatic glucose production. Similarly, hepatic glucoseproduction will be increased in type 1 diabetes, if the disease is notproperly controlled by insulin treatment.

Since existing forms of therapy of diabetes does not lead to sufficientglycemic control and therefore are unsatisfactory, there is a greatdemand for novel therapeutic approaches. Atherosclerosis, a disease ofthe arteries, is recognized to be the leading cause of death in theUnited States and Western Europe. The pathological sequence leading toatherosclerosis and occlusive heart disease is well known. The earlieststage in this sequence is the formation of “fatty streaks” in thecarotid, coronary and cerebral arteries and in the aorta. These lesionsare yellow in colour due to the presence of lipid deposits foundprincipally within smooth-muscle cells and in macrophages of the intimalayer of the arteries and aorta. Further, it is postulated that most ofthe cholesterol found within the fatty streaks, in turn, give rise todevelopment of the “fibrous plaque”, which consists of accumulatedintimal smooth muscle cells laden with lipid and surrounded byextra-cellular lipid, collagen, elastin and proteoglycans. The cellsplus matrix form a fibrous cap that covers a deeper deposit of celldebris and more extracellular lipid. The lipid is primarily free andesterified cholesterol. The fibrous plaque forms slowly, and is likelyin time to become calcified and necrotic, advancing to the “complicatedlesion” which accounts for the arterial occlusion and tendency towardmural thrombosis and arterial muscle spasm that characterize advancedatherosclerosis. Epidemiological evidence has firmly establishedhyperlipidemia as a primary risk factor in causing cardiovasculardisease (CVD) due to atherosclerosis. In recent years, leaders of themedical profession have placed renewed emphasis on lowering plasmacholesterol levels, and low density lipoprotein cholesterol inparticular, as an essential step in prevention of CVD. The upper limitsof “normal” are now known to be significantly lower than heretoforeappreciated. As a result, large segments of Western populations are nowrealized to be at particular high risk. Independent risk factors includeglucose intolerance, left ventricular hypertrophy, hypertension, andbeing of the male sex. Cardiovascular disease is especially prevalentamong diabetic subjects, at least in part because of the existence ofmultiple independent risk factors in this population. Successfultreatment of hyperlipidemia in the general population, and in diabeticsubjects in particular, is therefore of exceptional medical importance.

Hypertension (or high blood pressure) is a condition, which occurs inthe human population as a secondary symptom to various other disorderssuch as renal artery stenosis, pheochromocytoma, or endocrine disorders.However, hypertension is also evidenced in many patients in whom thecausative agent or disorder is unknown. While such “essential”hypertension is often associated with disorders such as obesity,diabetes, and hypertriglyceridemia, the relationship between thesedisorders has not been elucidated. Additionally, many patients displaythe symptoms of high blood pressure in the complete absence of any othersigns of disease or disorder.

It is known that hypertension can directly lead to heart failure, renalfailure, and stroke (brain hemorrhaging). These conditions are capableof causing short-term death in a patient. Hypertension can alsocontribute to the development of atherosclerosis and coronary disease.These conditions gradually weaken a patient and can lead to long-termdeath.

The exact cause of essential hypertension is unknown, though a number offactors are believed to contribute to the onset of the disease. Amongsuch factors are stress, uncontrolled emotions, unregulated hormonerelease (the renin, angiotensin aldosterone system), excessive salt andwater due to kidney malfunction, wall thickening and hypertrophy of thevasculature resulting in constricted blood vessels and genetic factors.

The treatment of essential hypertension has been undertaken bearing theforegoing factors in mind. Thus a broad range of beta-blockers,vasoconstrictors, angiotensin converting enzyme inhibitors and the likehave been developed and marketed as antihypertensives. The treatment ofhypertension utilizing these compounds has proven beneficial in theprevention of short-interval deaths such as heart failure, renalfailure, and brain hemorrhaging. However, the development ofatherosclerosis or heart disease due to hypertension over a long periodof time remains a problem. This implies that although high bloodpressure is being reduced, the underlying cause of essentialhypertension is not responding to this treatment. Hypertension has beenassociated with elevated blood insulin levels, a condition known ashyperinsulinemia. Insulin, a peptide hormone whose primary actions areto promote glucose utilization, protein synthesis and the formation andstorage of neutral lipids, also acts to promote vascular cell growth andincrease renal sodium retention, among other things. These latterfunctions can be accomplished without affecting glucose levels and areknown causes of hypertension. Peripheral vasculature growth, forexample, can cause constriction of peripheral capillaries, while sodiumretention increases blood volume. Thus, the lowering of insulin levelsin hyperinsulinemics can prevent abnormal vascular growth and renalsodium retention caused by high insulin levels and thereby alleviateshypertension.

Cardiac hypertrophy is a significant risk factor in the development ofsudden death, myocardial infarction, and congestive heart failure.Theses cardiac events are due, at least in part, to increasedsusceptibility to myocardial injury after ischemia and reperfusion,which can occur in out-patient as well as perioperative settings. Thereis an unmet medical need to prevent or minimize adverse myocardialperioperative outcomes, particularly perioperative myocardialinfarction. Both non-cardiac and cardiac surgery are associated withsubstantial risks for myocardial infarction or death. Some 7 millionpatients undergoing non-cardiac surgery are considered to be at risk,with incidences of perioperative death and serious cardiac complicationsas high as 20-25% in some series. In addition, of the 400,000 patientsundergoing coronary by-pass surgery annually, perioperative myocardialinfarction is estimated to occur in 5% and death in 1-2%. There iscurrently no drug therapy in this area, which reduces damage to cardiactissue from perioperative myocardial ischemia or enhances cardiacresistance to ischemic episodes. Such a therapy is anticipated to belife-saving and reduce hospitalizations, enhance quality of life andreduce overall health care costs of high risk patients. Obesity is awell-known risk factor for the development of many very common diseasessuch as atherosclerosis, hypertension, and diabetes. The incidence ofobese people and thereby also these diseases is increasing throughoutthe entire industrialised world. Except for exercise, diet and foodrestriction no convincing pharmacological treatment for reducing bodyweight effectively and acceptably currently exists. However, due to itsindirect but important effect as a risk factor in mortal and commondiseases it will be important to find treatment for obesity and/or meansof appetite regulation.

The term obesity implies an excess of adipose tissue. In this contextobesity is best viewed as any degree of excess adiposity that imparts ahealth risk. The cut off between normal and obese individuals can onlybe approximated, but the health risk imparted by the obesity is probablya continuum with increasing adiposity. The Framingham study demonstratedthat a 20% excess over desirable weight clearly imparted a health risk(Mann G V N. Engl. J. Med 291:226, 1974). In the United States aNational Institutes of Health consensus panel on obesity agreed that a20% increase in relative weight or a body mass index (BMI=body weight inkilograms divided by the square of the height in meters) above the 85thpercentile for young adults constitutes a health risk. By the use ofthese criteria 20 to 30 percent of adult men and 30 to 40 percent ofadult women in the United States are obese. (NIH, Ann Intern Med103:147, 1985).

Even mild obesity increases the risk for premature death, diabetes,hypertension, atherosclerosis, gallbladder disease, and certain types ofcancer. In the industrialised western world the prevalence of obesityhas increased significantly in the past few decades. Because of the highprevalence of obesity and its health consequences, its prevention andtreatment should be a high public health priority.

When energy intake exceeds expenditure, the excess calories are storedin adipose tissue, and if this net positive balance is prolonged,obesity results, i.e. there are two components to weight balance, and anabnormality on either side (intake or expenditure) can lead to obesity.The regulation of eating behaviour is incompletely understood. To someextent appetite is controlled by discrete areas in the hypothalamus: afeeding centre in the ventrolateral nucleus of the hypothalamus (VLH)and a satiety centre in the ventromedial hypothalamus (VMH). Thecerebral cortex receives positive signals from the feeding centre thatstimulate eating, and the satiety centre modulates this process bysending inhibitory impulses to the feeding centre. Several regulatoryprocesses may influence these hypothalamic centres. The satiety centremay be activated by the increases in plasma glucose and/or insulin thatfollow a meal. Meal-induced gastric distension is another possibleinhibitory factor. Additionally the hypothalamic centres are sensitiveto catecholamines, and beta-adrenergic stimulation inhibits eatingbehaviour. Ultimately, the cerebral cortex controls eating behaviour,and impulses from the feeding centre to the cerebral cortex are only oneinput. Psychological, social, and genetic factors also influence foodintake.

At present a variety of techniques are available to effect initialweight loss. Unfortunately, initial weight loss is not an optimaltherapeutic goal. Rather, the problem is that most obese patientseventually regain their weight. An effective means to establish and/orsustain weight loss is the major challenge in the treatment of obesitytoday.

SUMMARY OF THE INVENTION

The present invention provides compounds of general formula (1)

wherein the substituents are defined below, as well as furtherembodiments hereof described in the attached dependent claims.

The present invention also provides use of the compounds of theinvention for preparation of a medicament for the treatment of variousdiseases, e.g. for the treatment of type 2 diabetes.

DEFINITIONS

In the structural formulas given herein and throughout the presentspecification, the following terms have the indicated meaning:

The term “optionally substituted” as used herein means that the moietywhich is optionally substituted is either unsubstituted or substitutedwith one or more of the substituents specified. When the moiety inquestion is substituted with more than one substituent, the substituentmay be the same or different.

The term “adjacent” as used herein regards the relative positions of twoatoms or variables, these two atoms or variables sharing a bond or onevariable preceding or succeeding the other in a variable specification.By way of example, “atom A adjacent to atom B” means that the two atomsA and B share a bond.

The term “halogen” or “halo” means fluorine, chlorine, bromine oriodine.

The term “perhalomethyl” means trifluoromethyl, trichloromethyl,tribromomethyl, or triiodomethyl.

The use of prefixes of this structure: C_(x-y)-alkyl, C_(x-y)-alkenyl,C_(x-y)-alkynyl, C_(x-y)-cycloalyl orC_(x-y)-cycloalkyl-C_(x-y)-alkenyl- and the like designates radical ofthe designated type having from x to y carbon atoms.

The term “alkyl” as used herein, alone or in combination, refers to astraight or branched chain saturated monovalent hydrocarbon radicalhaving from one to ten carbon atoms, for example C₁₋₈-alkyl orC₁₋₆-alkyl. Typical C₁₋₈-alkyl groups and C₁₋₆-alkyl groups include, butare not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term“C₁₋₈-alkyl” as used herein also includes secondary C₃₋₈-alkyl andtertiary C₄₋₈-alkyl. The term “C₁₋₆-alkyl” as used herein also includessecondary C₃₋₆-alkyl and tertiary C₄₋₆-alkyl.

The term “alkenyl” as used herein, alone or in combination, refers to astraight or branched chain monovalent hydrocarbon radical containingfrom two to ten carbon atoms and at least one carbon-carbon double bond,for example C₂₋₈-alkenyl or C₂₋₆-alkenyl. Typical C₂₋₈-alkenyl groupsand C₂₋₆-alkenyl groups include, but are not limited to, vinyl,1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.

The term “alkynyl” as used herein alone or in combination, refers to astraight or branched monovalent hydrocarbon radical containing from twoto ten carbon atoms and at least one triple carbon-carbon bond, forexample C₂₋₈-alkynyl or C₂₋₆-alkynyl. Typical C₂₋₈-alkynyl groups andC₂₋₆-alkynyl groups include, but are not limited to, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,5-hexynyl, 2,4-hexadiynyl and the like.

The term “cycloalkyl” as used herein, alone or in combination, refers toa saturated mono-, bi-, or tricarbocyclic radical having from three totwelve carbon atoms, for example C₃₋₈-cycloalkyl. TypicalC₃₋₈-cycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl,adamantyl and the like.

The term “cycloalkenyl” as used herein, alone or in combination, refersto an non-aromatic unsaturated mono-, bi-, or tricarbocyclic radicalhaving from three to twelve carbon atoms, for example C₃₋₈-cycloalkenyl.Typical C₃₋₈-cycloalkyl groups include, but are not limited tocyclohexene, cycloheptene and cyclopentene, and the like.

The term “heterocyclic” or the term “heterocyclyl” as used herein, aloneor in combination, refers to a saturated mono-, bi-, or tricarbocyclicgroup having three to twelve carbon atoms and one or two additionalheteroatoms or groups selected from nitrogen, oxygen, sulphur, SO orSO₂, for example C₃₋₈-heterocyclyl. Typical C₃₋₈-heterocyclyl groupsinclude, but are not limited to, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, and the like.

The term “heterocycloalkenyl” as used herein, alone or in combination,refers to a non-aromatic unsaturated mono-, bi-, or tricyclic radicalhaving from three to twelve carbon atoms, and one or two additionalheteroatoms or groups selected from nitrogen, oxygen, sulphur, SO orSO₂, for example C₃₋₈-hetereocycloalkenyl. TypicalC₃₋₈-hetreocycloalkenyl groups include, but are not limited totetrahydropyridine, azacycloheptene, 2-pyrroline, 3-pyrroline,2-pyrazoline, imidazoline, 4H-pyran, and the like.

The term “alkoxy” as used herein, alone or in combination, refers to themonovalent radical R^(a)O—, where R^(a) is alkyl as defined above, forexample C₁₋₈-alkyl giving C₁₋₈-alkoxy. Typical C₁₋₈-alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxyand the like.

The term “alkylthio” as used herein, alone or in combination, refers toa straight or branched monovalent radical comprising an alkyl group asdescribed above linked through a divalent sulphur atom having its freevalence bond from the sulphur atom, for example C₁₋₆-alkylthio. TypicalC₁₋₆-alkylthio groups include, but are not limited to, methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

The term “alkoxycarbonyl” as used herein refers to the monovalentradical R^(a)OC(O)—, where R^(a) is alkyl as described above, forexample C₁₋₈-alkoxycarbonyl. Typical C₁₋₈-alkoxycarbonyl groups include,but are not limited to, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec-butoxycarbonyl, tertbutoxycarbonyl, 3-methylbutoxycarbonyl,n-hexoxycarbonyl and the like.

The term “aryl” as used herein refers to a carbocyclic aromatic ringradical or to a aromatic ring system radical. Aryl is also intended toinclude the partially hydrogenated derivatives of the carbocyclicsystems.

The term “heteroaryl”, as used herein, alone or in combination, refersto an aromatic ring radical with for instance 5 to 7 member atoms, or toa aromatic ring system radical with for instance from 7 to 18 memberatoms, containing one or more heteroatoms selected from nitrogen,oxygen, or sulphur heteroatoms, wherein N-oxides and sulphur monoxidesand sulphur dioxides are permissible heteroaromatic substitutions; suchas e.g. furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl,pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl,indolyl, and indazolyl, and the like. Heteroaryl is also intended toinclude the partially hydrogenated derivatives of the heterocyclicsystems enumerated below.

Examples of “aryl” and “heteroaryl” includes, but are not limited tophenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl),anthracene (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophene(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolin,fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl,pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), oxazolyl (2-oxazolyl,4-oxazolyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4-yl,isooxaz-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo-4-yl,isothiaz-5-yl) thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl),pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl(3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl),isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl(benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl,benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl),2,3-dihydro-benzo[b]thiophenyl (2,3-dihydro-benzo[b]thiophen-2-yl,2,3-dihydro-benzo[b]thiophen-3-yl, 2,3-dihydro-benzo[b]thiophen-4-yl,2,3-dihydro-benzo[b]thiophen-5-yl, 2,3-dihydro-benzo[b]thiophen-6-yl,2,3-dihydro-benzo[b]thiophen-7-yl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl,4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl),benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl,6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl,2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), benzo[1,3]dioxole(2-benzo[1,3]dioxole, 4-benzo[1,3]dioxole, 5-benzo[1,3]dioxole,6-benzo[1,3]dioxole, 7-benzo[1,3]dioxole), purinyl, and tetrazolyl(5-tetrazolyl, N-tetrazolyl).

The present invention also relates to partly or fully saturatedanalogues of the ring systems mentioned above.

When two or more of the above defined terms are used in combination,such as in aryl-alkyl, heteroaryl-alkyl, cycloalkyl-C₁₋₆-alkyl and thelike, it is to be understood that the first mentioned radical is asubstituent on the latter mentioned radical, where the point ofsubstitution, i.e. the point of attachment to another part of themolecule, is on the latter of the radicals, for example

The term “fused arylcycloalkyl”, as used herein, refers to an arylgroup, as defined above, fused to a cycloalkyl group, as defined aboveand having the indicated number of carbon atoms, the aryl and cycloalkylgroups having two atoms in common, and wherein the cycloalkyl group isthe point of substitution. Examples of “fused arylcycloalkyl” usedherein include 1-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl),

and the like.

The term “fused heteroarylcycloalkyl”, as used herein, refers to aheteroaryl group, as defined above, fused to a cycloalkyl group, asdefined above and having the indicated number of carbon atoms, the aryland cycloalkyl groups having two atoms in common, and wherein thecycloalkyl group is the point of substitution. Examples of fusedheteroarylcycloalkyl used herein include6,7-dihydro-5H-cyclopenta[b]pyridine, 5,6,7,8-tetrahydroquinoline,5,6,7,8-tetrahydrisoquinoline, 5,6,7,8-tetrahydroquinazoline and thelike

The term “alkylsulfanyl”, as used herein, refers to the group R^(a)S—,where R^(a) is alkyl as described above.

The term “alkylsulfenyl”, as used herein, refers to the groupR^(a)S(O)—, where R^(a) is alkyl as described above.

The term “alkylsulfonyl”, as used herein, refers to the group R^(a)SO₂—,where R^(a) is alkyl as described above.

The term “alkylsulfamoyl”, as used herein, refers to the groupR^(a)NHSO₂—, where R^(a) is alkyl as described above.

The term “dialkylsulfamoyl”, as used herein, refers to the groupR^(a)R^(b)NSO₂—, where R^(a) and R^(b) are alkyl as described above.

The term “alkylsulfinamoyl”, as used herein, refers to the groupR^(a)NHSO—, where R^(a) is alkyl as described above.

The term “dialkylsulfinamoyl”, as used herein, refers to the groupR^(a)R^(b)NSO—, where R^(a) and R^(b) are alkyl as described above.

The term “alkylamino”, as used herein, refers to the group R^(a)NH—,where R^(a) is alkyl as described above.

The term “acyl”, as used herein, refers to the group R^(a)C(O)—, whereR^(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl as described above.

The term “heteroaryloxy” as used herein, alone or in combination, refersto the monovalent radical R^(a)O—, where R^(a) is heteroaryl as definedabove.

The term “aryloxycarbonyl”, as used herein, refers to the groupR^(a)—O—C(O)—, where R^(a) is aryl as described above.

The term “acyloxy”, as used herein, refers to the group R^(a)C(O)O—,where R^(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl as described above.

The term “aryloxy”, as used herein refers to the group R^(a)—O—, whereR^(a) is aryl as described above.

The term “aroyloxy”, as used herein, refers to the group R^(a)C(O)O—,where R^(a) is aryl as described above.

The term “heteroaroyloxy”, as used herein, refers to the groupR^(a)C(O)O—, where R^(a) is heteroaryl as described above.

Whenever the terms “alkyl”, “cycloalkyl”, “aryl”, “heteroaryl” or thelike or either of their prefix roots appear in a name of a substituent(e.g. arylalkoxyaryloxy) they shall be interpreted as including thoselimitations given above for “alkyl” and “aryl”.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent—C(O)OH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “nitro” shall refer to the substituent —NO₂.

As used herein, the term “aminosulfonyl” shall refer to the substituent—SO₂NH₂.

As used herein, the term “sulfanyl” shall refer to the substituent —S—.

As used herein, the term “sulfenyl” shall refer to the substituent—S(O)—.

As used herein, the term “sulfonyl” shall refer to the substituent—S(O)₂—.

As used herein, the term “direct bond”, where part of a structuralvariable specification, refers to the direct joining of the substituentsflanking (preceding and succeeding) the variable taken as a “directbond”.

The term “lower”, as used herein, refers to an group having between oneand six carbons, and may be indicated with the prefix C_(x-6)—. Loweralkyl may thus be indicated as C₁₋₆-alkyl, while lower alkylene may beindicated as C₂₋₆-alkylene.

A radical such as C_(x-y)-cycloalkyl-C_(a-b)-alkenyl shall designatethat the radical's point of attachment is in part of the radicalmentioned last.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the term “attached” or “—” (e.g. —C(O)R¹¹ whichindicates the carbonyl attachment point to the scaffold) signifies astable covalent bond.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₃ and so forth.

Certain of the above defined terms may occur more than once in thestructural formulae, and upon such occurrence each term shall be definedindependently of the other.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)) and a solvent. Such solvents for the purpose of the presentinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the term “biohydrolyzable ester” is an ester of a drugsubstance (in this invention, a compound of formula (I)) which either a)does not interfere with the biological activity of the parent substancebut confers on that substance advantageous properties in vivo such asduration of action, onset of action, and the like, or b) is biologicallyinactive but is readily converted in vivo by the subject to thebiologically active principle. The advantage is that, for example, thebiohydrolyzable ester is orally absorbed from the gut and is transformedto (I) in plasma. Many examples of such are known in the art and includeby way of example lower alkyl esters (e.g., C₁₋₄), lower acyloxyalkylesters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylacylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drugsubstance (in this invention, a compound of general formula (I)) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable amide is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl amides, α-amino acid amides,alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides andbiohydrolyzable esters and also encompasses a) compounds in which thebiohydrolyzable functionality in such a prodrug is encompassed in thecompound of formula (I) and b) compounds which may be oxidized orreduced biologically at a given functional group to yield drugsubstances of formula (I). Examples of these functional groups include,but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like.

The term “pharmacologically effective amount” or shall mean that amountof a drug or pharmaceutical agent that will elicit the biological ormedical response of a tissue, animal or human that is being sought by aresearcher or clinician. This amount can be a therapeutically effectiveamount. The term “therapeutically effective amount” shall mean thatamount of a drug or pharmaceutical agent that will elicit thetherapeutic response of an animal or human that is being sought.

The term “treatment” and “treating” as used herein means the managementand care of a patient for the purpose of combating a disease, disorderor condition. The term is intended to include the full spectrum oftreatments for a given disorder from which the patient is suffering,such as the delaying of the progression of the disease, disorder orcondition, the alleviation or relief of symptoms and complications, theprevention of the disease and/or the cure or elimination of the disease,disorder or condition. The patient to be treated is preferably a mammal,in particular a human being.

DESCRIPTION OF THE INVENTION

The present invention provides compounds of general formula (I)

wherein R¹ is C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, or fusedaryl-C₃₋₈-cycloalkyl, each of which is optionally substituted with oneor more substituents R³, R⁴, R⁵ and R⁶;R² is C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, or fused aryl-C₃₋₈-cycloalkyl,each of which is optionally substituted with one or more substituentsR³⁰, R³¹, R³² and R³³, andA is heteroaryl, optionally substituted with one or more substituentsR⁷, R⁸ or R⁹, andR³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independently selected fromthe group consisting of

-   -   halogen, nitro, cyano, hydroxy, carboxy, —CF₃; or    -   —NR¹⁰R¹¹;    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,        heteroaryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        aryl-C₁₋₆-alkoxy, heteroaryl, heteroaryl-C₁₋₆-alkoxy, aryloxy,        heteroaryloxy, C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfenyl, arylsulfonyl,        heteroarylsulfonyl, acyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,        —C(O)—O—C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,        C₁₋₆-alkylthio-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyloxy, aroyl,        heteroaroyl, amino-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylsulfamoyl,        di(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylsulfinamoyl or        di(C₁₋₆-alkyl)sulfinamoyl each of which is optionally        substituted with one or more substituents independently selected        from R¹²; or    -   —C(O)—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or    -   two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—;        R¹⁰ and R¹¹ independently represent hydrogen, C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)OH,        —S(O)₂CH₃, or aryl;        R¹² is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl,        —S(O)₂CH₃, or —S(O)₂NH₂;        R¹³ and R¹⁴ are independently selected from the group consisting        of hydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        aryl, or heteroaryl, each of which is optionally substituted        with one or more substituents independently selected from R¹⁵;        or R¹³ and R¹⁴ together with the nitrogen to which they are        attached form a heterocycle such as piperazine, homopiperazine        or morpholine;        R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl,        —S(O)₂CH₃, or —S(O)₂NH₂;        A is heteroaryl which is optionally substituted with one or more        substituents independently selected from R⁷, R⁸ and R⁹;        R⁷, R⁸ and R⁹ are independently selected from    -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-alkylsulfonyl,        C₁₋₆-alkylsulfenyl, —C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —NH—C(O)—C₁₋₆-alkyl, —C₁₋₆-alkoxy-C₁₋₆-alkyl,        —C₁₋₆-alkyl-S—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, or        hydroxy-C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkylthio,        heteroaryl-C₁₋₆-alkylthio, heteroaryl-thio-C₁₋₆-alkyl, aryloxy,        heteroaryloxy, arylthio, heteroarylthio, arylsulfonyl,        heteroarylsulfonyl, aryl-C₁₋₆-alkylamino, each of which is        optionally substituted on the aryl or heteroaryl part with one        or more substituents independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, each of which is optionally        substituted on the cycloalkyl part with one or more substituents        independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,        —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹ wherein each alkyl        part may be substituted with one or more substituents        independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge;        R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen, nitro,        cyano, hydroxy, carboxy, —CF₃, carboxy-C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C(O)—O—C₁₋₆-alkyl, —S(O)₂CH₃, or —S(O)₂NH₂;        R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, heteroaryl or R¹⁷        and R¹⁸ together with the nitrogen to which they are attached        form a heterocycle such as piperazine, homopiperazine or        morpholine;        R²¹ is selected from    -   C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl or        hydroxy-C₁₋₆-alkyl; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, or heteroaryl-C₁₋₆-alkyl,        wherein the aryl or heteroaryl part is optionally substituted        with one or more substituents independently selected from R²⁴;        or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl.        R²² and R²³ are independently selected from hydrogen and        C₁₋₆-alkyl.        R²⁴ is halogen, nitro, cyano, hydroxy, carboxy, —CF₃,        C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, or carboxy-C₁₋₆-alkyl.        R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, nitro, cyano,        hydroxy, carboxy, —CF₃, —S(O)₂CH₃, or —S(O)₂NH₂        as well as any salt hereof with a pharmaceutically acceptable        acid or base, or any optical isomer or mixture of optical        isomers, including a racemic mixture, or any tautomeric forms.

In another embodiment R¹ is C₃₋₈-cycloalkyl, tetrahydrofuryl,tetrahydrothiofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl,adamantyl, tetrahydrofuryl, tetrahydrothiofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, adamantyl,tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, pyrrolidinyl,morpholinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is selected from

In another embodiment R¹ is selected from

In another embodiment R¹ is selected from

In another embodiment R² is C₃₋₈-cycloalkyl, tetrahydrofuryl,tetrahydrothiofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³⁰, R³¹R³² and R³³.

In another embodiment R² is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl,adamantyl, tetrahydrofuryl, tetrahydrothiofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents R³⁰, R³¹, R³² andR³³.

In another embodiment R² is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, adamantyl,tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³⁰, R³¹, R³² and R³³.

In another embodiment R² is cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, pyrrolidinyl,morpholinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents R³⁰, R³¹, R³² and R³³.

In another embodiment R² is selected from

In another embodiment R² is selected from

In another embodiment R² is selected from

In another embodiment R¹ and R² are both cyclohexyl.

In another embodiment R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ areindependently selected from the group consisting of

-   -   halogen, cyano, hydroxy, carboxy, —CF₃; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, C₁₋₆-alkylthio,        arylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl-carbonyl,        —C(O)—O—C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹²; or    -   —C(O)—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

In another embodiment R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ areindependently selected from the group consisting of halogen, —CF₃,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphtyl, benzyl,phenyl-ethyl, methoxy, ethoxy, phenylthio, methylsulfonyl,ethylsulfonyl, methylcarbonyl, ethylcarbonyl, —C(O)—O—CH₃,—C(O)—O—CH₂CH₃, each of which is optionally substituted with one or moresubstituents independently selected from R¹²; or

two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹, R³² andR³³ attached to the same or adjacent atoms together form a radical—O—(CH₂)₁₋₃—O—.

In another embodiment R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ areindependently selected from the group consisting of F, Cl, —CF₃, methyl,ethyl, propyl, isopropyl, butyl, or tert-butyl; or

two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹, R³² andR³³ attached to the same or adjacent atoms together form a radical—O—(CH₂)₁₋₃—O—.

In another embodiment R¹⁰ and R¹¹ independently represent hydrogen,methyl, ethyl, propyl, —C(O)—CH₃, —C(O)—CH₂CH₃, —CH₂C(O)OH,—CH₂CH₂C(O)OH, —C(O)—CH₂—C(O)OH, —C(O)—CH₂CH₂—C(O)OH, —S(O)₂CH₃, orphenyl.

In another embodiment R¹⁰ and R¹¹ independently represent hydrogen,methyl, ethyl, —C(O)—CH₃, —CH₂C(O)OH, —C(O)—CH₂—C(O)OH, —S(O)₂CH₃, orphenyl.

In another embodiment R¹⁰ and R¹¹ independently represent hydrogen,methyl, ethyl, or phenyl.

In another embodiment R¹² is halogen, cyano, hydroxy, carboxy, —CF₃, orC₁₋₆-alkyl.

In another embodiment R¹² is halogen, cyano, hydroxy, carboxy, —CF₃,methyl, ethyl or propyl.

In another embodiment R¹³ and R¹⁴ are independently selected from thegroup consisting of hydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, phenyl, or naphtyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁵; or

R¹³ and R¹⁴ together with the nitrogen to which they are attached form aheterocycle such as piperazine, homopiperazine or morpholine.

In another embodiment R¹³ and R¹⁴ are independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, hydroxy-methyl,hydroxy-ethyl, carboxy-methyl, carboxy-ethyl, phenyl, or naphtyl, eachof which is optionally substituted with one or more substituentsindependently selected from R¹⁵; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a heterocycle such aspiperazine, homopiperazine or morpholine.

In another embodiment R¹³ and R¹⁴ are independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, or phenyl, each ofwhich is optionally substituted with one or more substituentsindependently selected from R¹⁵.

In another embodiment R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃,methyl, ethyl, or propyl.

In another embodiment R¹⁵ is halogen, hydroxy, carboxy, —CF₃, methyl, orethyl.

In another embodiment A is thiazolyl, thiadiazolyl, pyrazinyl or4,5,6,7-tetrahydrobenzothiazolyl optionally substituted with one or moresubstituents independently selected from R⁷, R⁸ and R⁹.

In another embodiment A is

In another embodiment A is thiazolyl or thiadiazolyl optionallysubstituted with one or more substituents independently selected fromR⁷, R⁸ and R⁹.

In another embodiment A is thiazolyl, 1,2,4-thiadiazolyl, or1,3,4-thiadiazolyl, optionally substituted with one or more substituentsindependently selected from R⁷, R⁸ and R⁹.

In another embodiment A is

In another embodiment R⁷, R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₁₋₆-alkylamino, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfenyl,        —C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —NH—C(O)—C₁₋₆-alkyl, —C₁₋₆-alkoxy-C₁₋₆-alkyl,        —C₁₋₆-alkyl-S—C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio each        of which is optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, aryloxy,        heteroaryloxy, heteroarylthio, each of which is optionally        substituted on the aryl or heteroaryl part with one or more        substituents independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, each of which is optionally        substituted on the cycloalkyl part with one or more substituents        independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,        —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹ wherein each alkyl        part may be substituted with one or more substituents        independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

In another embodiment R⁷, R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy, cyano, or —CF₃; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₁₋₆-alkylsulfonyl, —C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of        which is optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, each        of which is optionally substituted on the aryl or heteroaryl        part with one or more substituents independently selected from        R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of which is        optionally substituted on the cycloalkyl part with one or more        substituents independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, wherein each alkyl part may be        substituted with one or more substituents independently selected        from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

In another embodiment R⁷, R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy or —CF₃; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl or        —C(O)—O—C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹⁶; or    -   phenyl, benzyl, or heteroarylthio, wherein heteroaryl is pyridyl        or imidazolyl, and wherein each aryl or heteroaryl is optionally        substituted on the aryl or heteroaryl part with one or more        substituents independently selected from R¹⁷; or    -   cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of        which is optionally substituted on the cycloalkyl part with one        or more substituents independently selected from R¹⁸; or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

In another embodiment R⁷, R⁸ and R⁹ are independently selected fromhalogen, carboxy, —CF₃, —S—CH₃, —S—CH₂CH₃, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₃,—CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃,—CH₂—O—C(O)—CH₃, —CH₂—O—C(O)—CH₂CH₃, —CH₂CH₂—O—C(O)—CH₃,—CH₂CH₂—O—C(O)—CH₂CH₃, —C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which isoptionally substituted with one or more substituents independentlyselected from R¹⁶; or heteroarylthio, wherein heteroaryl is pyridyl orimidazolyl, each optionally substituted on the heteroaryl part with oneor more substituents independently selected from R¹⁷.

In another embodiment R⁷, R⁸ and R⁹ are independently selected from Cl,F, Br, —CF₃, methyl, ethyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₂CH₃,—C(O)—O—CH₃, or —C(O)—O—CH₂CH₃; or heteroarylthio, wherein heteroaryl ispyridyl or imidazolyl, each optionally substituted on the heteroarylpart with one or more substituents independently selected from R¹⁷.

In another embodiment R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl,halogen, hydroxy, carboxy, —CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, or —S(O)₂CH₃.

In another embodiment R¹⁶, R¹⁷, and R¹⁸ are independently methyl, ethyl,propyl, halogen, hydroxy, carboxy, —CF₃, carboxy-methyl, carboxy-ethyl,carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl,—CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂—C(O)—O—CH₃,—CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃, —C(O)—O—CH₂CH₂CH₃,or —S(O)₂CH₃.

In another embodiment R¹⁶, R¹⁷, and R¹⁸ are independently methyl, ethyl,propyl, halogen, carboxy, carboxy-methyl, carboxy-ethyl, carboxy-propyl,hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, —CH₂—C(O)—O—CH₃,—CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃,—C(O)—O—CH₃, —C(O)—O—CH₂CH₃, —C(O)—O—CH₂CH₂CH₃, or —S(O)₂CH₃.

In another embodiment R¹⁹ and R²⁰ independently represent hydrogen,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, or naphtyl,or R¹⁷ and R¹⁸ together with the nitrogen to which they are attachedform a heterocycle such as piperazine, homopiperazine or morpholine.

In another embodiment R¹⁹ and R²⁰ independently represent hydrogen,methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl,hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, phenyl, or naphtyl, orR¹⁷ and R¹⁸ together with the nitrogen to which they are attached form aheterocycle such as piperazine, homopiperazine or morpholine.

In another embodiment R²¹ is selected from

-   -   C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, or hydroxy-C₁₋₆-alkyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

In another embodiment R²¹ is selected from

-   -   methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl,        carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl;        or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

In another embodiment R²¹ is selected from

-   -   methyl, ethyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴.

In another embodiment R²² and R²³ are independently selected fromhydrogen, methyl, ethyl, or propyl.

In another embodiment R²⁴ is halogen, hydroxy, carboxy, —CF₃, methyl,ethyl, propyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl,hydroxy-methyl, hydroxy-ethyl, or hydroxy-propyl.

In another embodiment R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen,hydroxy, carboxy, or —CF₃.

In another embodiment R²⁵ and R²⁶ are independently methyl, ethyl,propyl, halogen, hydroxy, carboxy, or —CF₃.

In another aspect the invention provides a compound of general formula(II)

wherein R¹ is C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, or fusedaryl-C₃₋₈-cycloalkyl, each of which is optionally substituted with oneor more substituents R³, R⁴, R⁵ and R⁶;R² is C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, or fused aryl-C₃₋₈-cycloalkyl,each of which is optionally substituted with one or more substituentsR³⁰, R³¹, R³² and R³³, andR³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independently selected fromthe group consisting of

-   -   halogen, nitro, cyano, hydroxy, oxo, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,        heteroaryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        aryl-C₁₋₆-alkoxy, heteroaryl, heteroaryl-C₁₋₆-alkoxy, aryloxy,        heteroaryloxy, C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfenyl, arylsulfonyl,        heteroarylsulfonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,        —C(O)—O—C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,        carboxy-C₁₋₆-alkyloxy, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylsulfamoyl, di(C₁₋₆-alkyl)sulfamoyl,        C₁₋₆-alkylsulfinamoyl or di(C₁₋₆-alkyl)sulfinamoyl each of which        is optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷, —C(O)—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or    -   two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—;        R¹⁰ and R¹¹ independently represent hydrogen, C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)OH,        —S(O)₂CH₃, or aryl;        R²⁷ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, heteroaryl,        heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,        R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹—N—C₁₋₆-alkyl,        R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl, R¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl,        C₁₋₆-alkyl-C(O)—NH—C₁₋₆-alkyl, aryl-C(O)—NH—C₁₋₆-alkyl,        heteroaryl-C(O)—NH—C₁₋₆-alkyl,        C₃₋₈-cycloalkyl-C(O)—NH—C₁₋₆-alkyl,        C₁₋₆-alkyl-S(O)₂—NH—C₁₋₆-alkyl, aryl-S(O)₂—NH—C₁₋₆-alkyl,        heteroaryl-S(O)₂—NH—C₁₋₆-alkyl, or        C₃₋₈-cycloalkyl-S(O)₂—NH—C₁₋₆-alkyl, each of which is optionally        substituted with one or more substituents independently selected        from R¹²;        R¹² is halogen, cyano, hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy,        —CF₃, C₁₋₆-alkyl, —S(O)₂CH₃, or —S(O)₂NH₂;        R¹³ and R¹⁴ are independently selected from the group consisting        of hydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        aryl, or heteroaryl, each of which is optionally substituted        with one or more substituents independently selected from R¹⁵;        or R¹³ and R¹⁴ together with the nitrogen to which they are        attached form a heterocycle such as piperazine, homopiperazine        or morpholine;        R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl,        —S(O)₂CH₃, or —S(O)₂NH₂;        A is heteroaryl which is optionally substituted with one or more        substituents independently selected from R⁷, R⁸ and R⁹;        R⁷, R⁸ and R⁹ are independently selected from    -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-alkylsulfonyl,        C₁₋₆-alkylsulfenyl, —C(O)—O—C₁₋₆-alkyl, formyl,        —C(O)—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl, —NH—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-S—C₁₋₆-alkyl,        carboxy-C₁₋₆-alkyl, or hydroxy-C₁₋₆-alkyl, each of which is        optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkylthio,        heteroaryl-C₁₋₆-alkylthio, heteroaryl-thio-C₁₋₆-alkyl, aryloxy,        heteroaryloxy, arylthio, heteroarylthio, arylsulfonyl,        heteroarylsulfonyl, aryl-C₁₋₆-alkylamino, each of which is        optionally substituted on the aryl or heteroaryl part with one        or more substituents independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, each of which is optionally        substituted on the cycloalkyl part with one or more substituents        independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,        —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰,        wherein each alkyl part may be substituted with one or more        substituents independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge;        R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen, nitro,        cyano, hydroxy, carboxy, —CF₃, carboxy-C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C(O)—O—C₁₋₆-alkyl, —NR¹⁹R²⁰, —NHS(O)₂CH₃, —C(O)NR¹⁹R²⁰,        —S(O)₂CH₃, or —S(O)₂NH₂;        R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, heteroaryl or R¹⁷        and R¹⁸ together with the nitrogen to which they are attached        form a heterocycle such as piperazine, homopiperazine or        morpholine;        R²¹ is selected from    -   C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl or        hydroxy-C₁₋₆-alkyl; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, or heteroaryl-C₁₋₆-alkyl,        wherein the aryl or heteroaryl part is optionally substituted        with one or more substituents independently selected from R²⁴;        or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl.        R²² and R²³ are independently selected from hydrogen,        C₁₋₆-alkyl, C₃₋₈-cycloalkyl, aryl, heteroaryl or R²² and R²³        together with the nitrogen to which they are attached form a        heterocycle such as pyrrolidine, piperidine or morpholine;        R²⁴ is halogen, nitro, cyano, hydroxy, carboxy, —CF₃,        C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, or carboxy-C₁₋₆-alkyl.        R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, nitro, cyano,        hydroxy, —C(O)—O—C₁₋₆-alkyl carboxy,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —CF₃,        —S(O)₂CH₃, or —S(O)₂NH₂ as well as any salt hereof with a        pharmaceutically acceptable acid or base, or any optical isomer        or mixture of optical isomers, including a racemic mixture, or        any tautomeric forms.

In one embodiment R¹ is C₃₋₈-cycloalkyl, tetrahydrofuryl,tetrahydrothiofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl,adamantyl, tetrahydrofuryl, tetrahydrothiofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, adamantyl,tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, pyrrolidinyl,morpholinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents R³, R⁴, R⁵ and R⁶.

In another embodiment R¹ is selected from

In another embodiment R¹ is selected from

In another embodiment R¹ is selected from

In another embodiment R¹ is selected from

In another embodiment R² is C₃₋₈-cycloalkyl, tetrahydrofuryl,tetrahydrothiofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³⁰, R³¹, R³² and R³³.

In another embodiment R² is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl,adamantyl, tetrahydrofuryl, tetrahydrothiofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents R³⁰, R³¹, R³² andR³³.

In another embodiment R² is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, adamantyl,tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³⁰, R³¹, R³² and R³³.

In another embodiment R² is cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, pyrrolidinyl,morpholinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents R³⁰, R³¹, R³² and R³³.

In another embodiment R² is selected from

In another embodiment R² is selected from

In another embodiment R² is selected from

In another embodiment R² is selected from

In another embodiment R¹ and R² are both cyclohexyl.

In another embodiment R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ areindependently selected from the group consisting of

-   -   halogen, oxo, cyano, hydroxy, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, C₁₋₆-alkylthio,        arylthio, C₁₋₆-alkylsulfonyl, —C(O)—O—C₁₋₆-alkyl, or        C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, each of which is optionally        substituted with one or more substituents independently selected        from R¹²; or    -   —C(O)—R²⁷, —C(O)—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

In another embodiment R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ areindependently selected from the group consisting of

-   -   halogen, oxo, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl,        aryl-C₁₋₆-alkyl, arylthio, C₁₋₆-alkylsulfonyl,        —C(O)—O—C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, each of which        is optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

In another embodiment R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ areindependently selected from the group consisting of

-   -   halogen, —CF₃; or    -   methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,        naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy, phenylthio,        methylsulfonyl, ethylsulfonyl, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃, each        of which is optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

In another embodiment R³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ areindependently selected from the group consisting of F, Cl, —CF₃, methyl,ethyl, propyl, isopropyl, butyl, or tert-butyl; or two substituentsselected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹, R³² and R³³ attached to thesame or adjacent atoms together form a radical —O—(CH₂)₁₋₃—O—.

In another embodiment R¹⁰ and R¹¹ independently represent hydrogen,methyl, ethyl, propyl, —C(O)—CH₃, —C(O)—CH₂CH₃, —CH₂C(O)OH,—CH₂CH₂C(O)OH, —C(O)—CH₂—C(O)OH, —C(O)—CH₂CH₂—C(O)OH, —S(O)₂CH₃, orphenyl.

In another embodiment R¹⁰ and R¹¹ independently represent hydrogen,methyl, ethyl, —C(O)—CH₃, —CH₂C(O)OH, —C(O)—CH₂—C(O)OH, —S(O)₂CH₃, orphenyl.

In another embodiment R¹⁰ and R¹¹ independently represent hydrogen,methyl, ethyl, or phenyl.

In another embodiment R²⁷ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,heteroaryl, heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹—N—C₁₋₆-alkyl, R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

In another embodiment R²⁷ is C₁₋₆-alkyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, heteroaryl, heteroaryl-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹—N—C₁₋₆-alkyl, R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

In another embodiment R²⁷ is C₁₋₆-alkyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl or heteroaryl, each of which isoptionally substituted with one or more substituents independentlyselected from R¹².

In another embodiment R²⁷ is methyl, ethyl, propyl, n-butyl, isobutyl,1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl,phenyl, pyridyl, thiophene, imidazole, or thiazole, each of which isoptionally substituted with one or more substituents independentlyselected from R¹².

In another embodiment R²⁷ is methyl, ethyl, propyl, n-butyl, isobutyl,1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl,phenyl, or pyridyl, thiophene, imidazole, or thiazole.

In another embodiment R¹² is halogen, cyano, hydroxy, carboxy, —CF₃, orC₁₋₆-alkyl.

In another embodiment R¹² is halogen, cyano, hydroxy, carboxy, —CF₃,methyl, ethyl or propyl.

In another embodiment R¹³ and R¹⁴ are independently selected from thegroup consisting of hydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, phenyl, or naphtyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁵; or R¹³ and R¹⁴ together with the nitrogen to which they areattached form a heterocycle such as piperazine, homopiperazine ormorpholine.

In another embodiment R¹³ and R¹⁴ are independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, hydroxy-methyl,hydroxy-ethyl, carboxy-methyl, carboxy-ethyl, phenyl, or naphtyl, eachof which is optionally substituted with one or more substituentsindependently selected from R¹⁵; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a heterocycle such aspiperazine, homopiperazine or morpholine.

In another embodiment R¹³ and R¹⁴ are independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, or phenyl, each ofwhich is optionally substituted with one or more substituentsindependently selected from R¹⁵.

In another embodiment R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃,methyl, ethyl, or propyl.

In another embodiment R¹⁵ is halogen, hydroxy, carboxy, —CF₃, methyl, orethyl.

In another embodiment A is thiazolyl, thiadiazolyl, pyrazinyl, pyridyl,5,6-dihydro-4H-cyclopentathiazolyl, or 4,5,6,7-tetrahydrobenzothiazolyloptionally substituted with one or more substituents independentlyselected from R⁷, R⁸ and R⁹.

In another embodiment A is

In another embodiment A is thiazolyl or thiadiazolyl optionallysubstituted with one or more substituents independently selected fromR⁷, R⁸ and R⁹.

In another embodiment A is thiazolyl, 1,2,3-thiadiazolyl, or1,3,4-thiadiazolyl, optionally substituted with one or more substituentsindependently selected from R⁷, R⁸ and R⁹.

In another embodiment A is

In another embodiment A is

In another embodiment R⁷, R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₁₋₆-alkylamino, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfenyl,        —C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —NH—C(O)—C₁₋₆-alkyl, —C₁₋₆-alkoxy-C₁₋₆-alkyl,        —C₁₋₆-alkyl-S—C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio each        of which is optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, aryloxy,        heteroaryloxy, heteroarylthio, each of which is optionally        substituted on the aryl or heteroaryl part with one or more        substituents independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, each of which is optionally        substituted on the cycloalkyl part with one or more substituents        independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,        —C₁₋₆-alkyl-S(O)—R²¹—C₁₋₆-alkyl-S(O)₂—R²¹ wherein each alkyl        part may be substituted with one or more substituents        independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

In another embodiment R⁷, R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy, cyano, or —CF₃; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₁₋₆-alkylsulfonyl, —C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of        which is optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, each        of which is optionally substituted on the aryl or heteroaryl        part with one or more substituents independently selected from        R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of which is        optionally substituted on the cycloalkyl part with one or more        substituents independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, wherein each alkyl part may be        substituted with one or more substituents independently selected        from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

In another embodiment R⁷, R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy or —CF₃; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl or        —C(O)—O—C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹⁶; or    -   phenyl, benzyl, or heteroarylthio, wherein heteroaryl is pyridyl        or imidazolyl, and wherein each aryl or heteroaryl is optionally        substituted on the aryl or heteroaryl part with one or more        substituents independently selected from R¹⁷; or    -   cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of        which is optionally substituted on the cycloalkyl part with one        or more substituents independently selected from R¹⁸; or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

In another embodiment R⁷, R⁸ and R⁹ are independently selected fromhalogen, carboxy, —CF₃, —S—CH₃, —S—CH₂CH₃, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₃,—CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃,—CH₂—O—C(O)—CH₃, —CH₂—O—C(O)—CH₂CH₃, —CH₂CH₂—O—C(O)—CH₃,—CH₂CH₂—O—C(O)—CH₂CH₃, —C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which isoptionally substituted with one or more substituents independentlyselected from R¹⁶; or heteroarylthio, wherein heteroaryl is pyridyl orimidazolyl, each optionally substituted on the heteroaryl part with oneor more substituents independently selected from R¹⁷.

In another embodiment R⁷, R⁸ and R⁹ are independently selected from Cl,F, Br, —CF₃, methyl, ethyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₂CH₃,—C(O)—O—CH₃, or —C(O)—O—CH₂CH₃; or heteroarylthio, wherein heteroaryl ispyridyl or imidazolyl, each optionally substituted on the heteroarylpart with one or more substituents independently selected from R¹⁷.

In another embodiment R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl,halogen, hydroxy, carboxy, —CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, or —S(O)₂CH₃.

In another embodiment R¹⁶, R¹⁷, and R¹⁸ are independently methyl, ethyl,propyl, halogen, hydroxy, carboxy, —CF₃, carboxy-methyl, carboxy-ethyl,carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl,—CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂—C(O)—O—CH₃,—CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃, —C(O)—O—CH₂CH₂CH₃,or —S(O)₂CH₃.

In another embodiment R¹⁶, R¹⁷, and R¹⁸ are independently methyl, ethyl,propyl, halogen, carboxy, carboxy-methyl, carboxy-ethyl, carboxy-propyl,hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, —CH₂—C(O)—O—CH₃,—CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃,—C(O)—O—CH₃, —C(O)—O—CH₂CH₃, —C(O)—O—CH₂CH₂CH₃, or —S(O)₂CH₃.

In another embodiment R¹⁹ and R²⁰ independently represent hydrogen,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, or naphtyl,or R¹⁹ and R²⁰ together with the nitrogen to which they are attachedform a heterocycle such as piperazine, homopiperazine or morpholine.

In another embodiment R¹⁹ and R²⁰ independently represent hydrogen,methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl,hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, phenyl, or naphtyl, orR¹⁹ and R²⁰ together with the nitrogen to which they are attached form aheterocycle such as piperazine, homopiperazine or morpholine.

In another embodiment R²¹ is selected from

-   -   C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, or hydroxy-C₁₋₆-alkyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

In another embodiment R²¹ is selected from

-   -   methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl,        carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl;        or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

In another embodiment R²¹ is selected from

-   -   methyl, ethyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴.

In another embodiment R²² and R²³ are independently selected fromhydrogen, methyl, ethyl, or propyl.

In another embodiment R²⁴ is halogen, hydroxy, carboxy, —CF₃, methyl,ethyl, propyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl,hydroxy-methyl, hydroxy-ethyl, or hydroxy-propyl.

In another embodiment R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen,hydroxy, carboxy, or —CF₃.

In another embodiment R²⁵ and R²⁶ are independently methyl, ethyl,propyl, halogen, hydroxy, carboxy, or —CF₃.

In another aspect the invention provides a compound as described hereinwhich is an activator of glucokinase, when tested in the GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of 2mM.

In another aspect the invention provides a compound as described hereinwhich is an activator of glucokinase, when tested in the GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of from10 to 15 mM.

In another aspect the invention provides a compound as described hereinwhich, at a concentration of 30 μM, is capable of providing an at least1.5, such as at least 1.7, for instance at least 2.0 fold activation ofglucokinase in the Glucokinase Activation Assay (I) disclosed herein ata glucose concentration of 2 mM.

In another aspect the invention provides a compound as described hereinwhich, at a concentration of 30 μM, is capable of providing an at least1.5, such as at least 1.7, for instance at least 2.0 fold activation ofglucokinase in the Glucokinase Activation Assay (I) disclosed herein ata glucose concentration of from 10 to 15 mM.

In another aspect the invention provides a compound as described hereinwhich, at a concentration of 5 μM is capable of providing an at least1.5, such as at least 1.7, for instance at least 2.0 fold activation ofglucokinase in the Glucokinase Activation Assay (I) disclosed herein ata glucose concentration of 2 mM.

In another aspect the invention provides a compound as described hereinwhich, at a concentration of 5 μM is capable of providing an at least1.5, such as at least 1.7, for instance at least 2.0 fold activation ofglucokinase in the Glucokinase Activation Assay (I) disclosed herein ata glucose concentration of from 10 to 15 mM.

In another aspect the invention provides a compound as described hereinwhich provides an increase in glucokinase activity, where the increasein glucokinase activity provided by the compound increases withincreasing concentrations of glucose.

In another aspect the invention provides a compound as described hereinwhich provides an increase in glucokinase activity in GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of 15mM, which increase is significantly higher than the increase inglucokinase activity provided by the compound in Glucokinase ActivationAssay (I) disclosed herein at a glucose concentration of 5 mM.

In another aspect the invention provides a compound as described hereinwhich, at a compound concentration of 10 μM provides an increase inglucokinase activity in Glucokinase Activation Assay (I) disclosedherein at a glucose concentration of 15 mM, which increase issignificantly higher than the increase in glucokinase activity providedby the compound at a compound concentration of 10 μM in GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of 5mM.

In another aspect the invention provides a compound as described hereinwhich, at a compound concentration of 10 μM provides an increase inglucokinase activity in Glucokinase Activation Assay (I) disclosedherein at a glucose concentration of 15 mM, which increase is at least1.1 fold higher, such as at least 1.2 fold higher, for instance at least1.3 fold higher, such as at least 1.4 fold higher, for instance 1.5 foldhigher, such as at least 1.6 fold higher, for instance at least 1.7 foldhigher, such as at least 1.8 fold higher, for instance at least 1.9 foldhigher, such as at least 2.0 fold higher than the increase inglucokinase activity provided by the compound at a compoundconcentration of 10 μM in Glucokinase Activation Assay (I) disclosedherein at a glucose concentration of 5 mM.

In another aspect the invention provides a compound as described herein,which compound increases glucose utilization in the liver withoutinducing any increase in insulin secretion in response to glucose.

In another aspect the invention provides a compound as described herein,which compound shows a significantly higher activity in isolatedhepatocytes compared to the activity of the compound in Ins-1 cells.

In another aspect the invention provides a compound as described herein,which compound shows a significantly higher activity in isolatedhepatocytes measured as described in the Glucokinase Activity Assay (II)compared to the activity of the compound in Ins-1 cells measured asdescribed in the Glucokinase Activity Assay (III).

In another aspect the invention provides a compound as described herein,which compound shows an activity in isolated hepatocytes measured asdescribed in the Glucokinase Activity Assay (II) which activity is atleast 1.1 fold higher, such as at least 1.2 fold higher, for instance atleast 1.3 fold higher, such as at least 1.4 fold higher, for instance1.5 fold higher, such as at least 1.6 fold higher, for instance at least1.7 fold higher, such as at least 1.8 fold higher, for instance at least1.9 fold higher, such as at least 2.0 fold higher, for instance at leasta 3.0 fold higher, such as at least a 4.0 fold higher, for instance atleast 5.0 fold higher, such as at least 10 fold higher than the activityof the compound in Ins-1 cells measured as described in the GlucokinaseActivity Assay (III).

In another aspect the invention provides a compound as described herein,which compound shows no activity in the Ins-1 cells measured asdescribed in the Glucokinase Activity Assay (III).

In another aspect the invention provides a method of preventinghypoglycemia comprising administration of a compound according to thepresent invention.

In another aspect the invention provides the use of a compound accordingto the present invention for the preparation of a medicament for theprevention of hypoglycemia.

In another aspect the invention provides a compound as described herein,which is an agent useful for the treatment of an indication selectedfrom the group consisting of hyperglycemia, IGT, insulin resistancesyndrome, syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia,hypertension, and obesity.

In another aspect the invention provides a compound as described hereinfor use as a medicament.

In another aspect the invention provides a compound as described hereinfor treatment of hyperglycemia, for treatment of IGT, for treatment ofSyndrome X, for treatment of type 2 diabetes, for treatment of type 1diabetes, for treatment of dyslipidemia, for treatment ofhyperlipidemia, for treatment of hypertension, for treatment of obesity,for lowering of food intake, for appetite regulation, for regulatingfeeding behaviour, or for enhancing the secretion of enteroincretins,such as GLP-1.

In another aspect the invention provides a pharmaceutical compositioncomprising, as an active ingredient, at least one compound as describedherein together with one or more pharmaceutically acceptable carriers orexcipients.

In one embodiment such a pharmaceutical composition may be in unitdosage form, comprising from about 0.05 mg to about 1000 mg, preferablyfrom about 0.1 mg to about 500 mg and especially preferred from about0.5 mg to about 200 mg of the compound according to the presentinvention.

In another aspect the invention provides the use of a compound accordingto the invention for increasing the activity of glucokinase.

In another aspect the invention provides the use of a compound accordingto the invention for the preparation of a medicament for the treatmentof metabolic disorders, for blood glucose lowering, for the treatment ofhyperglycemia, for the treatment of IGT, for the treatment of SyndromeX, for the treatment of impaired fasting glucose (IFG), for thetreatment of type 2 diabetes, for the treatment of type 1 diabetes, fordelaying the progression of impaired glucose tolerance (IGT) to type 2diabetes, for delaying the progression of non-insulin requiring type 2diabetes to insulin requiring type 2 diabetes, for the treatment ofdyslipidemia, for the treatment of hyperlipidemia, for the treatment ofhypertension, for lowering of food intake, for appetite regulation, forthe treatment of obesity, for regulating feeding behaviour, or forenhancing the secretion of enteroincretins. In another aspect theinvention provides the use of a compound according to the invention forthe preparation of a medicament for the adjuvant treatment of type 1diabetes for preventing the onset of diabetic complications.

In another aspect the invention provides the use of a compound accordingto the invention for the preparation of a medicament for increasing thenumber and/or the size of beta cells in a mammalian subject, fortreatment of beta cell degeneration, in particular apoptosis of betacells, or for treatment of functional dyspepsia, in particular irritablebowel syndrome.

In one embodiment the invention provides any of the above uses in aregimen which comprises treatment with a further antidiabetic agent.

In another embodiment the invention provides any of the above uses in aregimen which comprises treatment with a further antihyperlipidemicagent.

In another embodiment the invention provides any of the above uses in aregimen which comprises treatment with a further antiobesity agent.

In another embodiment the invention provides any of the above uses in aregimen which comprises treatment with a further antihypertensive agent.

In a further aspect the invention provides the use of a compoundaccording to the invention or a pharmaceutical composition as describedabove for the treatment of metabolic disorders, for blood glucoselowering, for the treatment of hyperglycemia, for treatment of IGT, fortreatment of Syndrome X, for the treatment of impaired fasting glucose(IFG), for treatment of type 2 diabetes, for treatment of type 1diabetes, for delaying the progression of impaired glucose tolerance(IGT) to type 2 diabetes, for delaying the progression of non-insulinrequiring type 2 diabetes to insulin requiring type 2 diabetes, fortreatment of dyslipidemia, for treatment of hyperlipidemia, fortreatment of hypertension, for the treatment or prophylaxis of obesity,for lowering of food intake, for appetite regulation, for regulatingfeeding behaviour, or for enhancing the secretion of enteroincretins.

In a further aspect the invention provides the use of a compoundaccording to the invention or a pharmaceutical composition as describedabove for the adjuvant treatment of type 1 diabetes for preventing theonset of diabetic complications.

In a further aspect the invention provides the use of a compoundaccording to the invention or a pharmaceutical composition as describedabove for increasing the number and/or the size of beta cells in amammalian subject, for treatment of beta cell degeneration, inparticular apoptosis of beta cells, or for treatment of functionaldyspepsia, in particular irritable bowel syndrome.

Embodiment 1

In a further aspect the invention provides a compound of general formula(I)

wherein R¹ is C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, or fusedaryl-C₃₋₈-cycloalkyl, each of which is optionally substituted with oneor more substituents R³, R⁴, R⁵ and R⁶;R² is C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, or fused aryl-C₃₋₈-cycloalkyl,each of which is optionally substituted with one or more substituentsR³⁰, R³¹, R³² and R³³, andR³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independently selected fromthe group consisting of

-   -   halogen, nitro, cyano, hydroxy, oxo, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,        heteroaryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        aryl-C₁₋₆-alkoxy, heteroaryl, heteroaryl-C₁₋₆-alkoxy, aryloxy,        heteroaryloxy, C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylsulfenyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,        C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,        C₁₋₆-alkylthio-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyloxy,        amino-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylsulfamoyl,        di(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylsulfinamoyl or        di(C₁₋₆-alkyl)sulfinamoyl each of which is optionally        substituted with one or more substituents independently selected        from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴;        or    -   two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—;        R¹⁰ and R¹¹ independently represent hydrogen, C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)OH,        —S(O)₂CH₃, or aryl;        R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,        aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, heteroaryl,        heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,        R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹—N—C₁₋₆-alkyl,        R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl, R¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl,        C₁₋₆-alkyl-C(O)—NH—C₁₋₆-alkyl, aryl-C(O)—NH—C₁₋₆-alkyl,        heteroaryl-C(O)—NH—C₁₋₆-alkyl,        C₃₋₈-cycloalkyl-C(O)—NH—C₁₋₆-alkyl,        C₁₋₆-alkyl-S(O)₂—NH—C₁₋₆-alkyl, aryl-S(O)₂—NH—C₁₋₆-alkyl,        heteroaryl-S(O)₂—NH—C₁₋₆-alkyl, or        C₃₋₈-cycloalkyl-S(O)₂—NH—C₁₋₆-alkyl, each of which is optionally        substituted with one or more substituents independently selected        from R¹²;        R¹² is halogen, cyano, hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy,        —CF₃, C₁₋₆-alkyl, C₁₋₆-alkoxy, —S(O)₂CH₃, or —S(O)₂NH₂;        R¹³ and R¹⁴ are independently selected from the group consisting        of hydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        aryl, or heteroaryl, each of which is optionally substituted        with one or more substituents independently selected from R¹⁵;        or R¹³ and R¹⁴ together with the nitrogen to which they are        attached form a 3 to 8 membered heterocyclic ring with the said        nitrogen atom, the heterocyclic ring optionally containing one        or two further heteroatoms selected from nitrogen, oxygen and        sulphur;        R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl,        —S(O)₂CH₃, or —S(O)₂NH₂;        A is heteroaryl which is optionally substituted with one or more        substituents independently selected from R⁷, R⁸ and R⁹;        R⁷, R⁸ and R⁹ are independently selected from    -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-alkylsulfenyl,        —C(O)—O—C₁₋₆-alkyl, formyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —NH—C(O)—C₁₋₆-alkyl, —C₁₋₆-alkoxy-C₁₋₆-alkyl,        —C₁₋₆-alkyl-S—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, or        hydroxy-C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkylthio,        heteroaryl-C₁₋₆-alkylthio, heteroaryl-thio-C₁₋₆-alkyl, aryloxy,        heteroaryloxy, arylthio, heteroarylthio, aryl-C₁₋₆-alkylamino,        each of which is optionally substituted on the aryl or        heteroaryl part with one or more substituents independently        selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, each of which is optionally        substituted on the cycloalkyl part with one or more substituents        independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,        —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹, —S(O)₂—R²¹ or        —S(O)₂—NR¹⁹R²⁰, wherein each alkyl part may be substituted with        one or more substituents independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge;        R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen, nitro,        cyano, hydroxy, carboxy, oxo, —CF₃, carboxy-C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C(O)—O—C₁₋₆-alkyl, —NR¹⁹R²⁰, —NHS(O)₂CH₃, —C(O)NR¹⁹R²⁰,        —S(O)₂CH₃, or —S(O)₂NH₂;        R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, heteroaryl,        C₃₋₈-heterocyclyl, or —S(O)₂—C₁₋₆-alkyl, each of which is        optionally substituted with one or more substituents        independently selected from R²⁴, or R¹⁹ and R²⁰ together with        the nitrogen to which they are attached form a 3 to 8 membered        heterocyclic ring with the said nitrogen atom, the heterocyclic        ring optionally containing one or two further heteroatoms        selected from nitrogen, oxygen and sulphur, the heterocyclic        ring is optionally substituted with one or more substituents        independently selected from R²⁴;        R²¹ is selected from    -   C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl or        hydroxy-C₁₋₆-alkyl; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, or heteroaryl-C₁₋₆-alkyl,        wherein the aryl or heteroaryl part is optionally substituted        with one or more substituents independently selected from R²⁴;        or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl;        R²² and R²³ are independently selected from hydrogen,        C₁₋₆-alkyl, C₃₋₈-cycloalkyl, aryl, heteroaryl or R²² and R²³        together with the nitrogen to which they are attached form a 3        to 8 membered heterocyclic ring with the said nitrogen atom, the        heterocyclic ring optionally containing one or two further        heteroatoms selected from nitrogen, oxygen and sulphur, the        heterocyclic ring is optionally substituted with one or more        substituents independently selected from R²⁴;        R²⁴ is halogen, nitro, cyano, hydroxy, carboxy, —CF₃,        C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl or        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl;        R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, nitro, cyano,        hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —CF₃,        —S(O)₂CH₃, or —S(O)₂NH₂ as well as any salt hereof with a        pharmaceutically acceptable acid or base, or any optical isomer        or mixture of optical isomers, including a racemic mixture, or        any tautomeric forms.

Embodiment 2

A compound according to embodiment 1 wherein R¹ is C₃₋₈-cycloalkyl,indanyl, tetrahydrofuryl, tetrahydrothiofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.

Embodiment 3

A compound according to any one of the embodiments 1 to 2 wherein R¹ iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl, bicyclo[3.2.1]octyl,bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl, adamantyl, indanyl,tetrahydrofuryl, tetrahydrothiofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.

Embodiment 4

A compound according to embodiment 3 wherein R¹ is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.2.1]octyl,bicyclo[2.2.1]heptyl, adamantyl, indanyl, tetrahydrofuryl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³, R⁴, R⁵ and R⁶.

Embodiment 5

A compound according to embodiment 4 wherein R¹ is cyclopentyl,cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, tetrahydrofuryl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³, R⁴, R⁵ and R⁶.

Embodiment 6

A compound according to embodiment 5 wherein R¹ is selected from

7. A compound according to embodiment 6 wherein R¹ is selected from

Embodiment 8

A compound according to embodiment 7 wherein R¹ is selected from

Embodiment 9

A compound according to embodiment 8 wherein R¹ is selected from

Embodiment 10

A compound according to embodiment 9 wherein R¹ is selected from

Embodiment 11

A compound according to embodiment 10 wherein R¹ is

Embodiment 12

A compound according to embodiment 10 wherein R¹ is

Embodiment 13

A compound according to embodiment 10 wherein R¹ is

Embodiment 14

A compound according to any one of the embodiments 1 to 13 wherein R² isC₃₋₈-cycloalkyl, tetrahydrofuryl, tetrahydrothiofuryl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,1,4-dioxanyl, 1,3-dioxanyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³⁰, R³¹, R³² and R³³.

Embodiment 15

A compound according to embodiment 14 wherein R² is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl,norpinyl, norbonyl, norcaryl, adamantyl, tetrahydrofuryl,tetrahydrothiofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment 16

A compound according to embodiment 15 wherein R² is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.2.1]octyl,bicyclo[2.2.1]heptyl, adamantyl, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, pyrrolidinyl,morpholinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment 17

A compound according to embodiment 16 wherein R² is cyclopentyl,cyclohexyl, bicyclo[2.2.1]heptyl, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, pyrrolidinyl,morpholinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment 18

A compound according to embodiment 17 wherein R² is selected from

Embodiment 19

A compound according to embodiment 18 wherein R² is selected from

Embodiment 20

A compound according to embodiment 19 wherein R² is selected from

Embodiment 21

A compound according to embodiment 20 wherein R² is selected from

Embodiment 22

A compound according to embodiment 21 wherein R² is selected from

Embodiment 23

A compound according to embodiment 22 wherein R² is

Embodiment 24

A compound according to embodiment 22 wherein R² is

Embodiment 25

A compound according to embodiment 22 wherein R² is

Embodiment 26

A compound according to any one of the embodiments 1 to 25 wherein R¹and R² are both cyclohexyl.

Embodiment 27

A compound according to any one of the embodiments 1 to 26 wherein R³,R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independently selected from thegroup consisting of

-   -   halogen, oxo, cyano, hydroxy, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, C₁₋₆-alkylthio,        arylthio, —C(O)—O—C₁₋₆-alkyl, or C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        each of which is optionally substituted with one or more        substituents independently selected from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴;        or two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

Embodiment 28

A compound according to embodiment 27 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of

-   -   halogen, oxo, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl,        aryl-C₁₋₆-alkyl, arylthio, —C(O)—O—C₁₋₆-alkyl, or        C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, each of which is optionally        substituted with one or more substituents independently selected        from R¹²; or    -   —C(O)—R²⁷ or —S(O)₂—R²⁷; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

Embodiment 29

A compound according to embodiment 28 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of

-   -   halogen, —CF₃; or    -   methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,        naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy, propoxy,        phenylthio, —C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which is        optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷ or —S(O)₂—R²⁷; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

Embodiment 30

A compound according to embodiment 29 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of

-   -   halogen, —CF₃; or    -   methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,        naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy, propoxy,        phenylthio, —C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which is        optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷ or —S(O)₂—R²⁷.

Embodiment 31

A compound according to embodiment 30 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of F,Cl, —CF₃, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl,—C(O)—R²⁷ or —S(O)₂—R²⁷.

Embodiment 32

A compound according to embodiment 28 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from C₁₋₆-alkyl or —C(O)—R²⁷.

Embodiment 33

A compound according to any one of the embodiments 1 to 32 wherein R¹⁰and R¹¹ independently represent hydrogen, methyl, ethyl, propyl,—C(O)—CH₃, —C(O)—CH₂CH₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —C(O)—CH₂—C(O)OH,—C(O)—CH₂CH₂—C(O)OH, —S(O)₂CH₃, or phenyl.

Embodiment 34

A compound according to embodiment 33 wherein R¹⁰ and R¹¹ independentlyrepresent hydrogen, methyl, ethyl, —C(O)—CH₃, —CH₂C(O)OH,—C(O)—CH₂—C(O)OH, —S(O)₂CH₃, or phenyl.

Embodiment 35

A compound according to embodiment 34 wherein R¹⁰ and R¹¹ independentlyrepresent hydrogen, methyl, ethyl, or phenyl.

Embodiment 36

A compound according to any one of the embodiments 1 to 35 wherein R²⁷is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl,heteroaryl, heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

Embodiment 37

A compound according to embodiment 36 wherein R²⁷ is C₁₋₆-alkyl,C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,aryl-C₂₋₆-alkenyl, aryl, heteroaryl, heteroaryl-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

Embodiment 38

A compound according to embodiment 37 wherein R²⁷ is C₁₋₆-alkyl,C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,heteroaryl-C₁₋₆-alkyl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl orheteroaryl, each of which is optionally substituted with one or moresubstituents independently selected from R¹².

Embodiment 39

A compound according to embodiment 38 wherein R²⁷ is methyl, ethyl,propyl, n-butyl, isobutyl, 1,1,1-trifluoroethyl, cyclopropyl,cyclopentyl, cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole,or thiazole, each of which is optionally substituted with one or moresubstituents independently selected from R¹².

Embodiment 40

A compound according to embodiment 39 wherein R²⁷ is methyl, ethyl,propyl, n-butyl, isobutyl, 1,1,1-trifluoroethyl, cyclopropyl,cyclopentyl, cyclopropylmethyl, phenyl, or pyridyl, thiophene,imidazole, or thiazole.

Embodiment 41

A compound according to any one of the embodiments 1 to 40 wherein R¹²is halogen, cyano, hydroxy, carboxy, —CF₃, or C₁₋₆-alkyl.

Embodiment 42

A compound according to embodiment 41 wherein R¹² is halogen, cyano,hydroxy, carboxy, —CF₃, methoxy, methyl, ethyl or propyl.

Embodiment 43

A compound according to any one of the embodiments 1 to 42 wherein R¹³and R¹⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, ornaphtyl, each of which is optionally substituted with one or moresubstituents independently selected from R¹⁵; or R¹³ and R¹⁴ togetherwith the nitrogen to which they are attached form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom, the heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur.

Embodiment 44

A compound according to embodiment 43 wherein R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen, methyl,ethyl, propyl, hydroxy-methyl, hydroxy-ethyl, carboxy-methyl,carboxy-ethyl, phenyl, or naphtyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁵; or R¹³ and R¹⁴ together with the nitrogen to which they areattached form a 3 to 8 membered heterocyclic ring with the said nitrogenatom, the heterocyclic ring optionally containing one or two furtherheteroatoms selected from nitrogen, oxygen and sulphur.

Embodiment 45

A compound according to embodiment 44 wherein R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen, methyl,ethyl, propyl, or phenyl, each of which is optionally substituted withone or more substituents independently selected from R¹⁵.

Embodiment 46

A compound according to any one of the embodiments 1 to 44 wherein R¹⁵is halogen, cyano, hydroxy, carboxy, —CF₃, methyl, ethyl, or propyl.

Embodiment 47

A compound according to embodiment 46 wherein R¹⁵ is halogen, hydroxy,carboxy, —CF₃, methyl, or ethyl.

Embodiment 48

A compound according to any one of the embodiments 1 to 47 wherein A isthiazolyl, thiadiazolyl, pyrazinyl, pyridyl, benzothiazolyl,5,6-dihydro-4H-cyclopentathiazolyl,4,5,6,7-tetrahydro-benzothiazolo-pyridyl, 6,7-dihydro-pyranothiazolyl,or 4,5,6,7-tetrahydrobenzothiazolyl optionally substituted with one ormore substituents independently selected from R⁷, R⁸ and R⁹.

Embodiment 49

A compound according to embodiment 48 wherein A is

Embodiment 50

A compound according to embodiment 48 wherein A is thiazolyl orthiadiazolyl optionally substituted with one or more substituentsindependently selected from R⁷, R³ and R⁹.

Embodiment 51

A compound according to embodiment 50 wherein A is thiazolyl,1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl, optionally substituted withone or more substituents independently selected from R⁷, R⁸ and R⁹.

Embodiment 52

A compound according to embodiment 51 wherein A is

Embodiment 53

A compound according to embodiment 52 wherein A is

Embodiment 54

A compound according to embodiment 53 wherein A is

Embodiment 55

A compound according to any one of the embodiments 1 to 54 wherein R⁷,R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₁₋₆-alkylamino, C₁₋₆-alkylsulfenyl, —C(O)—O—C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl, —NH—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-S—C₁₋₆-alkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio each of which is optionally        substituted with one or more substituents independently selected        from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy,        heteroaryl-thio-C₁₋₆-alkyl, aryloxy, heteroaryloxy,        heteroarylthio, each of which is optionally substituted on the        aryl or heteroaryl part with one or more substituents        independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, each of which is optionally        substituted on the cycloalkyl part with one or more substituents        independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,        —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹, —S(O)₂—R²¹ or        —S(O)₂—NR¹⁹R²⁰, wherein each alkyl part may be substituted with        one or more substituents independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

Embodiment 56

A compound according to embodiment 55 wherein R⁷, R⁸ and R⁹ areindependently selected from

-   -   halogen, carboxy, cyano, or —CF₃; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        —C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of        which is optionally substituted with one or more substituents        independently selected from R¹⁶; or aryl, heteroaryl,        aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, each of which is        optionally substituted on the aryl or heteroaryl part with one        or more substituents independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of which is        optionally substituted on the cycloalkyl part with one or more        substituents independently selected from R¹⁸; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰,        wherein each alkyl part may be substituted with one or more        substituents independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

Embodiment 57

A compound according to embodiment 56 wherein R⁷, R⁸ and R⁹ areindependently selected from

-   -   halogen, carboxy or —CF₃; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl or        —C(O)—O—C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹⁶; or    -   phenyl, benzyl, or heteroarylthio, wherein heteroaryl is pyridyl        or imidazolyl, and wherein each aryl or heteroaryl is optionally        substituted on the aryl or heteroaryl part with one or more        substituents independently selected from R¹⁷; or    -   cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of        which is optionally substituted on the cycloalkyl part with one        or more substituents independently selected from R¹⁸; or    -   —C(O)NR²²R²³, —S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰; or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

Embodiment 58

A compound according to embodiment 57 wherein R⁷, R⁸ and R⁹ areindependently selected from halogen, carboxy, —CF₃, —S—CH₃, —S—CH₂CH₃,—S—CH₂CH₂CH₃, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,methoxy, ethoxy, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —CH₂—O—C(O)—CH₃,—CH₂—O—C(O)—CH₂CH₃, —CH₂CH₂—O—C(O)—CH₃, —CH₂CH₂—O—C(O)—CH₂CH₃,—C(O)—O—CH₃, —C(O)—O—CH₂CH₃, each of which is optionally substitutedwith one or more substituents independently selected from R¹⁶; orheteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, eachoptionally substituted on the heteroaryl part with one or moresubstituents independently selected from R¹⁷, or —S(O)₂—R²¹.

Embodiment 59

A compound according to embodiment 58 wherein R⁷, R⁸ and R⁹ areindependently selected from Cl, F, Br, —CF₃, —S—CH₃, —S—CH₂CH₃,—S—CH₂CH₂CH₃, methyl, ethyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₂CH₃,—C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which is optionally substitutedwith one or more substituents independently selected from R¹⁶; orheteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, eachoptionally substituted on the heteroaryl part with one or moresubstituents independently selected from R¹⁷.

Embodiment 60

A compound according to any one of the embodiments 1 to 59 wherein R¹⁶,R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen, hydroxy, oxo,carboxy, —CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, —NR¹⁹R²⁰,—C(O)NR¹⁹R²⁰ or —S(O)₂CH₃.

Embodiment 61

A compound according to embodiment 60 wherein R¹⁶, R¹⁷, and R¹⁸ areindependently methyl, ethyl, propyl, halogen, hydroxy, oxo, carboxy,—CF₃, carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl,hydroxy-ethyl, hydroxy-propyl, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃,—C(O)—O—CH₂CH₂CH₃, or —S(O)₂CH₃.

Embodiment 62

A compound according to embodiment 61 wherein R¹⁶, R¹⁷, and R¹⁸ areindependently methyl, ethyl, propyl, halogen, oxo, carboxy,carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl,hydroxy-ethyl, hydroxy-propyl, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃,—C(O)—O—CH₂CH₂CH₃, or —S(O)₂CH₃.

Embodiment 63

A compound according to embodiment 60 wherein R¹⁶, R¹⁷, and R¹⁸ areindependently carboxy, —NR¹⁹R²⁰, or —C(O)NR¹⁹R²⁰.

Embodiment 64

A compound according to any one of the embodiments 1 to 63 wherein R¹⁹and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, naphtyl,C₃₋₈-heterocyclyl, or —S(O)₂—C₁₋₆-alkyl, each of which is optionallysubstituted with one or more substituents independently selected fromR²⁴; or R¹⁹ and R²⁰ together with the nitrogen to which they areattached form a 3 to 8 membered heterocyclic ring with the said nitrogenatom, the heterocyclic ring optionally containing one or two furtherheteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclicring is optionally substituted with one or more substituentsindependently selected from R²⁴.

Embodiment 65

A compound according to embodiment 64 wherein R¹⁹ and R²⁰ independentlyrepresent hydrogen, methyl, ethyl, propyl, carboxy-methyl,carboxy-ethyl, carboxy-propyl, hydroxy-methyl, hydroxy-ethyl,hydroxy-propyl, phenyl, or naphtyl, or R¹⁹ and R²⁰ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment 66

A compound according to embodiment 64 wherein R¹⁹ and R²⁰ independentlyrepresent hydrogen, C₁₋₆-alkyl, or R¹⁹ and R²⁰ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment 67

A compound according to embodiment 66 wherein R¹⁹ and R²⁰ independentlyrepresent hydrogen, methyl, ethyl, or propyl, or R¹⁹ and R²⁰ togetherwith the nitrogen to which they are attached form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom, wherein the heterocyclicring is pyrrolidyl, piperidyl, piperazinyl, homopiperazinyl, ormorpholinyl, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment 68

A compound according to any one of the embodiments 1 to 67 wherein R²¹is selected from

-   -   C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, or hydroxy-C₁₋₆-alkyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

Embodiment 69

A compound according to embodiment 68 wherein R²¹ is selected from

-   -   methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl,        carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl;        or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

Embodiment 70

A compound according to embodiment 69 wherein R²¹ is selected from

-   -   methyl, ethyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴.

Embodiment 71

A compound according to any one of the embodiments 1 to 70 wherein R²²and R²³ are independently selected from hydrogen, C₁₋₆-alkyl,C₃₋₈-cycloalkyl, phenyl, naphtyl, or R²² and R²³ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment 72

A compound according to embodiment 71 wherein R²² and R²³ areindependently selected from hydrogen, methyl, ethyl, propyl, butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl,naphtyl, or R²² and R²³ together with the nitrogen to which they areattached form a 3 to 8 membered heterocyclic ring with the said nitrogenatom, wherein the heterocyclic ring is pyrrolidyl, piperidyl,piperazinyl, homopiperazinyl, or morpholinyl, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴.

Embodiment 73

A compound according to any one of the embodiments 1 to 72 wherein R²⁴is halogen, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl or—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl.

Embodiment 74

A compound according to embodiment 73 wherein R²⁴ is carboxy,C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl or—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl.

Embodiment 75

A compound according to any one of the embodiments 1 to wherein R²⁵ andR²⁶ are independently C₁₋₆-alkyl, halogen, hydroxy, carboxy, or —CF₃.

Embodiment 76

A compound according to embodiment 75 wherein R²⁵ and R²⁶ areindependently methyl, ethyl, propyl, halogen, hydroxy, carboxy, or —CF₃.

Embodiment 77

A compound according to any one of the embodiments 1 to 76, whichcompound is an activator of glucokinase, when tested in the GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of 2mM.

Embodiment 78

A compound according to any one of the embodiments 1 to 77, whichcompound is an activator of glucokinase, when tested in the GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of from10 to 15 mM.

Embodiment 79

A compound according to any one of the embodiments 1 to 78, whichcompound, at a concentration of 30 μM, is capable of providing an atleast 1.5, such as at least 1.7, for instance at least 2.0 foldactivation of glucokinase in the Glucokinase Activation Assay (I)disclosed herein at a glucose concentration of 2 mM.

Embodiment 80

A compound according to any one of the embodiments 1 to 79, whichcompound, at a concentration of 30 μM, is capable of providing an atleast 1.5, such as at least 1.7, for instance at least 2.0 foldactivation of glucokinase in the Glucokinase Activation Assay (I)disclosed herein at a glucose concentration of from 10 to 15 mM.

Embodiment 81

A compound according to any one of the embodiments 1 to 80, which at aconcentration of 5 μM is capable of providing an at least 1.5, such asat least 1.7, for instance at least 2.0 fold activation of glucokinasein the Glucokinase Activation Assay (I) disclosed herein at a glucoseconcentration of 2 mM.

Embodiment 82

A compound according to any one of the embodiments 1 to 81, which at aconcentration of 5 μM is capable of providing an at least 1.5, such asat least 1.7, for instance at least 2.0 fold activation of glucokinasein the Glucokinase Activation Assay (I) disclosed herein at a glucoseconcentration of from 10 to 15 mM.

Embodiment 83

A compound according to any one of the embodiments 1 to 82, whichcompound provides an increase in glucokinase activity, where theincrease in glucokinase activity provided by the compound increases withincreasing concentrations of glucose.

Embodiment 84

A compound according to embodiment 83, which provides an increase inglucokinase activity in Glucokinase Activation Assay (I) disclosedherein at a glucose concentration of 15 mM, which increase issignificantly higher than the increase in glucokinase activity providedby the compound in Glucokinase Activation Assay (I) disclosed herein ata glucose concentration of 5 mM.

Embodiment 85

A compound according to any one of the embodiments 83 to 84, which at acompound concentration of 10 μM provides an increase in glucokinaseactivity in Glucokinase Activation Assay (I) disclosed herein at aglucose concentration of 15 mM, which increase is significantly higherthan the increase in glucokinase activity provided by the compound at acompound concentration of 10 μM in Glucokinase Activation Assay (I)disclosed herein at a glucose concentration of 5 mM.

Embodiment 86

A compound according to any one of the embodiments 83 to 85, which at acompound concentration of 10 μM provides an increase in glucokinaseactivity in Glucokinase Activation Assay (I) disclosed herein at aglucose concentration of 15 mM, which increase is at least 1.1 foldhigher, such as at least 1.2 fold higher, for instance at least 1.3 foldhigher, such as at least 1.4 fold higher, for instance 1.5 fold higher,such as at least 1.6 fold higher, for instance at least 1.7 fold higher,such as at least 1.8 fold higher, for instance at least 1.9 fold higher,such as at least 2.0 fold higher than the increase in glucokinaseactivity provided by the compound at a compound concentration of 10 μMin Glucokinase Activation Assay (I) disclosed herein at a glucoseconcentration of 5 mM.

Embodiment Liver Specificity

87. A compound according to any one of the embodiments 1 to 86, whichcompound increases glucose utilization in the liver without inducing anyincrease in insulin secretion in response to glucose.

Embodiment 88

A compound according to any one of the embodiments 1 to 86, whichcompound shows a significantly higher activity in isolated hepatocytescompared to the activity of the compound in Ins-1 cells.

Embodiment 89

A compound according to any one of the embodiments 87 to 88, whichcompound shows a significantly higher activity in isolated hepatocytesmeasured as described in the Glucokinase Activity Assay (II) compared tothe activity of the compound in Ins-1 cells measured as described in theGlucokinase Activity Assay (III).

Embodiment 90

A compound according to embodiment 89, which compound shows an activityin isolated hepatocytes measured as described in the GlucokinaseActivity Assay (II) which activity is at least 1.1 fold higher, such asat least 1.2 fold higher, for instance at least 1.3 fold higher, such asat least 1.4 fold higher, for instance 1.5 fold higher, such as at least1.6 fold higher, for instance at least 1.7 fold higher, such as at least1.8 fold higher, for instance at least 1.9 fold higher, such as at least2.0 fold higher, for instance at least a 3.0 fold higher, such as atleast a 4.0 fold higher, for instance at least 5.0 fold higher, such asat least 10 fold higher than the activity of the compound in Ins-1 cellsmeasured as described in the Glucokinase Activity Assay (III).

Embodiment 91

A compound according to embodiment 89, which compound shows no activityin the Ins-1 cells measured as described in the Glucokinase ActivityAssay (III).

Embodiment 92

A method of preventing hypoglycemia comprising administration of acompound according to any one of the embodiments 1 to 91.

Embodiment 93

The use of a compound according to any one of the embodiments 1 to 91for the preparation of a medicament for the prevention of hypoglycemia.

Embodiment 94

A compound according to any one of embodiments 1 to 91, which is anagent useful for the treatment of an indication selected from the groupconsisting of hyperglycemia, IGT, insulin resistance syndrome, syndromeX, type 2 diabetes, type 1 diabetes, dyslipidemia, hypertension, andobesity.

Embodiment 95

A compound according to any one of embodiments 1 to 94 for use as amedicament.

Embodiment 96

A compound according to any one of embodiments 1 to 94 for treatment ofhyperglycemia, for treatment of IGT, for treatment of Syndrome X, fortreatment of type 2 diabetes, for treatment of type 1 diabetes, fortreatment of dyslipidemia, for treatment of hyperlipidemia, fortreatment of hypertension, for treatment of obesity, for lowering offood intake, for appetite regulation, for regulating feeding behaviour,or for enhancing the secretion of enteroincretins, such as GLP-1.

Embodiment 97

A pharmaceutical composition comprising, as an active ingredient, atleast one compound according to any one of embodiments 1 to 96 togetherwith one or more pharmaceutically acceptable carriers or excipients.

Embodiment 98

A pharmaceutical composition according to embodiment 97 in unit dosageform, comprising from about 0.05 mg to about 1000 mg, preferably fromabout 0.1 mg to about 500 mg and especially preferred from about 0.5 mgto about 200 mg of the compound according to any one of embodiments 1 to96.

Embodiment 99

Use of a compound according to any one of the embodiments 1 to 96 forincreasing the activity of glucokinase.

Embodiment 100

Use of a compound according to any one of embodiments 1 to 96 for thepreparation of a medicament for the treatment of metabolic disorders,for blood glucose lowering, for the treatment of hyperglycemia, for thetreatment of IGT, for the treatment of Syndrome X, for the treatment ofimpaired fasting glucose (IFG), for the treatment of type 2 diabetes,for the treatment of type 1 diabetes, for delaying the progression ofimpaired glucose tolerance (IGT) to type 2 diabetes, for delaying theprogression of non-insulin requiring type 2 diabetes to insulinrequiring type 2 diabetes, for the treatment of dyslipidemia, for thetreatment of hyperlipidemia, for the treatment of hypertension, forlowering of food intake, for appetite regulation, for the treatment ofobesity, for regulating feeding behaviour, or for enhancing thesecretion of enteroincretins.

Embodiment 101

Use of a compound according to any one of embodiments 1 to 96 for thepreparation of a medicament for the adjuvant treatment of type 1diabetes for preventing the onset of diabetic complications.

Embodiment 102

Use of a compound according to any one of embodiments 1 to 96 for thepreparation of a medicament for increasing the number and/or the size ofbeta cells in a mammalian subject, for treatment of beta celldegeneration, in particular apoptosis of beta cells, or for treatment offunctional dyspepsia, in particular irritable bowel syndrome.

Embodiment 103

Use according to any one of the embodiments 100 to 102 in a regimenwhich comprises treatment with a further antidiabetic agent.

Embodiment 104

Use according to any one of the embodiments 100 to 103 in a regimenwhich comprises treatment with a further antihyperlipidemic agent.

Embodiment 105

Use according to any one of embodiments 100 to 104 in a regimen whichcomprises treatment with a further antiobesity agent.

Embodiment 106

Use according to any one of embodiments 100 to 105 in a regimen whichcomprises treatment with a further antihypertensive agent.

Embodiment 107

Use of a compound according to any one of the embodiments 1 to 96 or apharmaceutical composition according to embodiment 97 or embodiment 98for the treatment of metabolic disorders, for blood glucose lowering,for the treatment of hyperglycemia, for treatment of IGT, for treatmentof Syndrome X, for the treatment of impaired fasting glucose (IFG), fortreatment of type 2 diabetes, for treatment of type 1 diabetes, fordelaying the progression of impaired glucose tolerance (IGT) to type 2diabetes, for delaying the progression of non-insulin requiring type 2diabetes to insulin requiring type 2 diabetes, for treatment ofdyslipidemia, for treatment of hyperlipidemia, for treatment ofhypertension, for the treatment or prophylaxis of obesity, for loweringof food intake, for appetite regulation, for regulating feedingbehaviour, or for enhancing the secretion of enteroincretins.

Embodiment 108

Use of a compound according to any one of the embodiments 1 to 96 or apharmaceutical composition according to embodiment 97 or embodiment 98for the adjuvant treatment of type 1 diabetes for preventing the onsetof diabetic complications.

Embodiment 109

Use of a compound according to any one of the embodiments 1 to 96 or apharmaceutical composition according to embodiment 97 or embodiment 98for increasing the number and/or the size of beta cells in a mammaliansubject, for treatment of beta cell degeneration, in particularapoptosis of beta cells, or for treatment of functional dyspepsia, inparticular irritable bowel syndrome.

Embodiment A1

In another aspect the invention provides a compound of general formula(I)

wherein R¹ is C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-heterocyclyl,C₃₋₈-heterocycloalkenyl, fused aryl-C₃₋₈-cycloalkyl, or fusedheteroaryl-C₃₋₈-cycloalkyl, each of which is optionally substituted withone or more substituents R³, R⁴, R⁵ and R⁶;R² is C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-heterocyclyl,C₃₋₈-heterocycloalkenyl, fused aryl-C₃₋₈-cycloalkyl or fusedheteroaryl-C₃₋₈-cycloalkyl, each of which is optionally substituted withone or more substituents R³⁰, R³¹, R³² and R³³, andR³, R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independently selected fromthe group consisting of

-   -   halogen, nitro, cyano, hydroxy, oxo, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,        heteroaryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        aryl-C₁₋₆-alkoxy, heteroaryl, heteroaryl-C₁₋₆-alkoxy, aryloxy,        heteroaryloxy, C₁₋₆-alkylthio, arylthio, heteroarylthio,        C₃₋₈-cycloalkylthio, aryl-C₁₋₆-alkylthio,        heteroaryl-C₁₋₆-alkylthio, C₁₋₆-alkylsulfenyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,        carboxy-C₁₋₆-alkyloxy, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylsulfamoyl, di(C₁₋₆-alkyl)sulfamoyl,        C₁₋₆-alkylsulfinamoyl or di(C₁₋₆-alkyl)sulfinamoyl each of which        is optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —S(O)₂—NR¹³R¹⁴,        —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or    -   two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—;        R¹⁰ and R¹¹ independently represent hydrogen, C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl-C(O)OH, —S(O)₂—C₁₋₆-alkyl, or aryl;        R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, aryl, aryl-C₁₋₆-alkyl,        aryloxy-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, heteroaryl,        C₃₋₈-heterocyclyl, heteroaryl-C₁₋₆-alkyl,        C₃₋₈-heterocyclyl-C₁₋₆-alkyl, heteroaryloxy-C₁₋₆-alkyl,        carboxy-C₁₋₆-alkyl, carboxy-C₂₋₆-alkenyl,        C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₂₋₆-alkenyl,        C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,        R¹⁰R¹¹—N—C₁₋₆-alkyl, R¹⁰R¹¹—N—C₂₋₆-alkenyl,        R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl, R¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl,        C₁₋₆-alkyl-C(O)—NH—C₁₋₆-alkyl, aryl-C(O)—NH—C₁₋₆-alkyl,        heteroaryl-C(O)—NH—C₁₋₆-alkyl,        C₃₋₈-cycloalkyl-C(O)—NH—C₁₋₆-alkyl,        C₁₋₆-alkyl-S(O)₂—NH—C₁₋₆-alkyl, aryl-S(O)₂—NH—C₁₋₆-alkyl,        heteroaryl-S(O)₂—NH—C₁₋₆-alkyl, or        C₃₋₈-cycloalkyl-S(O)₂—NH—C₁₋₆-alkyl, each of which is optionally        substituted with one or more substituents independently selected        from R¹²;        R¹² is halogen, cyano, hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy,        —CF₃, C₁₋₆-alkyl, C₁₋₆-alkoxy, —NR¹⁰R¹¹, —S(O)₂CH₃, or        —S(O)₂NH₂;        R¹³ and R¹⁴ are independently selected from the group consisting        of hydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        aryl, or heteroaryl, each of which is optionally substituted        with one or more substituents independently selected from R¹⁵;        or R¹³ and R¹⁴ together with the nitrogen to which they are        attached form a 3 to 8 membered heterocyclic ring with the said        nitrogen atom, the heterocyclic ring optionally containing one        or two further heteroatoms selected from nitrogen, oxygen and        sulphur;        R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl,        —S(O)₂CH₃, or —S(O)₂NH₂;        A is heteroaryl which is optionally substituted with one or more        substituents independently selected from R⁷, R⁸ and R⁹;        R⁷, R⁸ and R⁹ are independently selected from    -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,        C₁₋₆-alkylthio, C₂₋₆-alkenylthio, C₁₋₆-alkylamino,        C₁₋₆-alkylsulfenyl, —C(O)—O—C₁₋₆-alkyl, formyl,        —C(O)—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl, —NH—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-S—C₁₋₆-alkyl,        carboxy-C₁₋₆-alkyl, or hydroxy-C₁₋₆-alkyl, each of which is        optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkylthio,        heteroaryl-C₁₋₆-alkylthio, heteroaryl-thio-C₁₋₆-alkyl,        heteroaryl-oxy-C₁₋₆-alkyl, aryloxy, heteroaryloxy, arylthio,        heteroarylthio, aryl-C₁₋₆-alkylamino, —C(O)-aryl, or        —C(O)-heteroaryl, each of which is optionally substituted on the        aryl or heteroaryl part with one or more substituents        independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkylthio,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,        each of which is optionally substituted on the cycloalkyl part        with one or more substituents independently selected from R¹⁸;        or    -   C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,        C₃₋₈-heterocyclyl-C₁₋₆-alkylthio, C₃₋₈-heterocyclylthio,        C₃₋₈-heterocyclyl-amino-C₁₋₆-alkyl, or —C(O)—C₃₋₈-heterocyclyl,        each of which is optionally substituted with one or more        substituents independently selected from R¹⁶; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₂₋₆-alkenyl-NR¹⁹R²⁰,        —C₁₋₆-alkyl-S—R²¹, —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹,        —S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰, wherein each alkyl part may be        substituted with one or more substituents independently selected        from R²⁵; or    -   —C(O)NR²²R²³—C₁₋₆-alkyl-C(O)NR²²R²³—C₁₋₆-alkyl-NH—NR²²R²³—C₁₋₆-alkyl-NH—C(O)—C₁₋₆-alkyl-NR²²R²³,        each optionally substituted with one or more substituents        independently selected from R²⁶; or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge; the C₂₋₅-alkylene bridge is optionally        substituted with one or more substituents independently selected        from R¹⁶;        R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen, nitro,        cyano, hydroxy, carboxy, oxo, —CF₃, carboxy-C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—NR¹⁹R²⁰, —C(O)—O—C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl-C(O)—C₁₋₆-alkyl, —NR¹⁹R²⁰, —NHS(O)₂C₁₋₆-alkyl,        —C(O)NR¹⁹R²⁰, —S(O)₂C₁₋₆-alkyl, or —S(O)₂NR¹⁹R²⁰;        R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,        hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, heteroaryl,        C₃₋₈-heterocyclyl, aryl-C₁₋₆-alkyl,        C₃₋₈-heterocyclyl-C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³, or        —S(O)₂—C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R²⁴, or R¹⁹        and R²⁰ together with the nitrogen to which they are attached        form a 3 to 8 membered heterocyclic ring with the said nitrogen        atom, the heterocyclic ring optionally containing one or two        further heteroatoms selected from nitrogen, oxygen and sulphur,        the heterocyclic ring is optionally substituted with one or more        substituents independently selected from R²⁴;        R²¹ is selected from    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, carboxy-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl or hydroxy-C₁₋₆-alkyl,        —C₁₋₆-alkyl-NR²²R²³; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, or heteroaryl-C₁₋₆-alkyl,        wherein the aryl or heteroaryl part is optionally substituted        with one or more substituents independently selected from R²⁴;        or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl;        R²² and R²³ are independently selected from hydrogen,        C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-S(O)₂—C₁₋₆-alkyl,        C₃₋₈-cycloalkyl, aryl, or heteroaryl; or R²² and R²³ together        with the nitrogen to which they are attached form a 3 to 8        membered heterocyclic ring with the said nitrogen atom, the        heterocyclic ring optionally containing one or two further        heteroatoms selected from nitrogen, oxygen and sulphur, the        heterocyclic ring is optionally substituted with one or more        substituents independently selected from R²⁴;        R²⁴ is halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF₃,        C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, —C(O)—C₃₋₈-cycloalkyl, —C(O)-aryl,        —C(O)-heteroaryl, —C(O)—C₃₋₈-heterocyclyl —C(O)—O—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, aryl, heteroaryl,        aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl,        C₃₋₈-heterocyclyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-heterocyclyl-C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—C₃₋₈-heterocyclyl, —C(O)—O—C₁₋₆-alkyl-aryl,        —NH—S(O)₂R², or —S(O)₂R², wherein each cyclic moiety is        optionally substituted with one or more substituents        independently selected from R²⁹;        R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, nitro, cyano,        hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —CF₃,        —S(O)₂CH₃, or —S(O)₂NH₂;        R²⁸ is C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, C₃₋₈-cycloalkyl, aryl,        aryl-C₁₋₆-alkyl, heteroaryl optionally substituted with        C₁₋₆-alkyl, —NH₂, or —N(CH₃)₂;        R²⁹ is halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF₃,        C₁₋₆-alkyl, or C₁₋₆-alkoxy;        as well as any salt hereof with a pharmaceutically acceptable        acid or base, or any optical isomer or mixture of optical        isomers, including a racemic mixture, or any tautomeric forms.

Embodiment A2

A compound according to embodiment A1 wherein R¹ is C₃₋₈-cycloalkyl,C₃₋₈-cycloalkenyl, indanyl, tetrahydrofuryl, tetrahydrothiofuryl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,1,4-dioxanyl, 1,3-dioxanyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³, R⁴, R⁵ and R⁶.

Embodiment A3

A compound according to any one of the embodiments A1 to A2 wherein R¹is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl, bicyclo[3.2.1]octyl,bicyclo[2.2.1]heptyl, norpinyl, norbonyl, norcaryl, adamantyl, indanyl,tetrahydrofuryl, tetrahydrothiofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl,piperidyl, pyrrolidinyl, morpholinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents R³, R⁴, R⁵ and R⁶.

Embodiment A4

A compound according to embodiment A3 wherein R¹ is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl,bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, adamantyl, indanyl,tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³, R⁴, R⁵ and R⁶.

Embodiment A5

A compound according to embodiment A4 wherein R¹ is cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo[2.2.1]heptyl,tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidyl, pyrrolidinyl, morpholinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents R³, R⁴, R⁵ and R⁶.

Embodiment A6

A compound according to embodiment A5 wherein R¹ is selected from

Embodiment A7

A compound according to embodiment A6 wherein R¹ is selected from

Embodiment A8

A compound according to embodiment A7 wherein R¹ is selected from

Embodiment A9

A compound according to embodiment A8 wherein R¹ is selected from

Embodiment A10

A compound according to embodiment A9 wherein R¹ is selected from

Embodiment A11

A compound according to embodiment A10 wherein R¹ is

Embodiment A12

A compound according to embodiment A10 wherein R¹ is

Embodiment A13

A compound according to embodiment A10 wherein R¹ is

Embodiment A14

A compound according to any one of the embodiments A1 to A13 wherein R²is C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, tetrahydrofuryl,tetrahydrothiofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment A15

A compound according to embodiment A14 wherein R² is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl,norpinyl, norbonyl, norcaryl, adamantyl, tetrahydrofuryl,tetrahydrothiofuryl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment A16

A compound according to embodiment A15 wherein R² is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[3.2.1]octyl,bicyclo[2.2.1]heptyl, adamantyl, tetrahydrofuryl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, pyrrolidinyl,morpholinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment A17

A compound according to embodiment A16 wherein R² is cyclopentyl,cyclohexyl, cyclohexenyl, bicyclo[2.2.1]heptyl, tetrahydrofuryl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl,pyrrolidinyl, morpholinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents R³⁰, R³¹, R³² and R³³.

Embodiment A18

A compound according to embodiment A17 wherein R² is selected from

Embodiment A19

A compound according to embodiment A18 wherein R² is selected from

Embodiment A20

A compound according to embodiment A19 wherein R² is selected from

Embodiment A21

A compound according to embodiment A20 wherein R² is selected from

Embodiment A22

A compound according to embodiment A21 wherein R² is selected from

Embodiment A23

A compound according to embodiment A22 wherein R² is

Embodiment A24

A compound according to embodiment A22 wherein R² is

Embodiment A25

A compound according to embodiment A22 wherein R² is

Embodiment A26

A compound according to any one of the embodiments A1 to A25 wherein R¹and R² are both cyclohexyl.

Embodiment A27

A compound according to any one of the embodiments A1 to A25 wherein R¹is

and R² is cyclohexyl.

Embodiment A28

A compound according to any one of the embodiments A1 to A27 wherein R³,R⁴, R⁵, R⁶, R³⁰, R³¹, R³² and R³³ are independently selected from thegroup consisting of

-   -   halogen, oxo, cyano, hydroxy, carboxy, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, C₁₋₆-alkylthio,        arylthio, —C(O)—O—C₁₋₆-alkyl, or C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        each of which is optionally substituted with one or more        substituents independently selected from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —S(O)₂—NR¹³R¹⁴,        —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

Embodiment A29

A compound according to embodiment A28 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of

-   -   halogen, oxo, —CF₃; or    -   —NR¹⁰R¹¹; or    -   C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl,        aryl-C₁₋₆-alkyl, arylthio, —C(O)—O—C₁₋₆-alkyl, or        C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, each of which is optionally        substituted with one or more substituents independently selected        from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—NR¹³R¹⁴ or —S(O)₂—R²⁷; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

Embodiment A30

A compound according to embodiment A29 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of

-   -   halogen, —CF₃; or    -   methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,        naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy, propoxy,        phenylthio, —C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which is        optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—NR¹³R¹⁴ or —S(O)₂—R²⁷; or        two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰, R³¹,        R³² and R³³ attached to the same or adjacent atoms together form        a radical —O—(CH₂)₁₋₃—O—.

Embodiment A31

A compound according to embodiment A30 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of

-   -   halogen, —CF₃; or    -   methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,        naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy, propoxy,        phenylthio, —C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which is        optionally substituted with one or more substituents        independently selected from R¹²; or    -   —C(O)—R²⁷, —S(O)₂—NR¹³R¹⁴ or —S(O)₂—R²⁷.

Embodiment A32

A compound according to embodiment A31 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from the group consisting of F,Cl, —CF₃, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy,ethoxy, propoxy, —C(O)—R²⁷, —S(O)₂—NR¹³R¹⁴ or —S(O)₂—R²⁷.

Embodiment A33

A compound according to embodiment A29 wherein R³, R⁴, R⁵, R⁶, R³⁰, R³¹,R³² and R³³ are independently selected from C₁₋₆-alkyl, C₁₋₆-alkoxy,—S(O)₂—R²⁷ or —C(O)—R²⁷.

Embodiment A34

A compound according to any one of the embodiments A1 to A33 wherein R¹⁰and R¹¹ independently represent hydrogen, methyl, ethyl, propyl,—C(O)—CH₃, —C(O)—CH₂CH₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —C(O)—CH₂—C(O)OH,—C(O)—CH₂CH₂—C(O)OH, —S(O)₂CH₃, or phenyl.

Embodiment A35

A compound according to embodiment A34 wherein R¹⁰ and R¹¹ independentlyrepresent hydrogen, methyl, ethyl, —C(O)—CH₃, —CH₂C(O)OH,—C(O)—CH₂—C(O)OH, —S(O)₂CH₃, or phenyl.

Embodiment A36

A compound according to embodiment A35 wherein R¹⁰ and R¹¹ independentlyrepresent hydrogen, methyl, ethyl, or phenyl.

Embodiment A37

A compound according to any one of the embodiments A1 to A36 wherein R²⁷is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl,heteroaryl, heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

Embodiment A38

A compound according to embodiment A37 wherein R²⁷ is C₁₋₆-alkyl,C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,aryl-C₂₋₆-alkenyl, aryl, heteroaryl, heteroaryl-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².

Embodiment A39

A compound according to embodiment A38 wherein R²⁷ is C₁₋₆-alkyl,C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,heteroaryl-C₁₋₆-alkyl, aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, or heteroaryl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹².

Embodiment A40

A compound according to embodiment A39 wherein R²⁷ is methyl, ethyl,propyl, n-butyl, isobutyl, 1,1,1-trifluoroethyl, cyclopropyl,cyclopentyl, cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole,or thiazole, each of which is optionally substituted with one or moresubstituents independently selected from R¹².

Embodiment A41

A compound according to embodiment A40 wherein R²⁷ is methyl, ethyl,propyl, n-butyl, isobutyl, 1,1,1-trifluoroethyl, cyclopropyl,cyclopentyl, cyclopropylmethyl, phenyl, or pyridyl, thiophene,imidazole, or thiazole.

Embodiment A42

A compound according to any one of the embodiments A1 to A41 wherein R¹²is halogen, cyano, hydroxy, carboxy, —CF₃, or C₁₋₆-alkyl.

Embodiment A43

A compound according to embodiment A42 wherein R¹² is halogen, cyano,hydroxy, carboxy, —CF₃, methoxy, methyl, ethyl or propyl.

Embodiment A44

A compound according to embodiment A43 wherein R¹² is halogen, carboxy,methyl, ethyl or propyl.

Embodiment A45

A compound according to any one of the embodiments A1 to A44 wherein R¹³and R¹⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, ornaphtyl, each of which is optionally substituted with one or moresubstituents independently selected from R¹⁵; or R¹³ and R¹⁴ togetherwith the nitrogen to which they are attached form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom, the heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur.

Embodiment A46

A compound according to embodiment A45 wherein R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen, methyl,ethyl, propyl, hydroxy-methyl, hydroxy-ethyl, carboxy-methyl,carboxy-ethyl, phenyl, or naphtyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁵; or R¹³ and R¹⁴ together with the nitrogen to which they areattached form a 3 to 8 membered heterocyclic ring with the said nitrogenatom, the heterocyclic ring optionally containing one or two furtherheteroatoms selected from nitrogen, oxygen and sulphur.

Embodiment A47

A compound according to embodiment A46 wherein R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen, methyl,ethyl, propyl, or phenyl, each of which is optionally substituted withone or more substituents independently selected from R¹⁵.

Embodiment A48

A compound according to any one of the embodiments A1 to A46 wherein R¹⁵is halogen, cyano, hydroxy, carboxy, —CF₃, methyl, ethyl, or propyl.

Embodiment A49

A compound according to embodiment A48 wherein R¹⁵ is halogen, hydroxy,carboxy, —CF₃, methyl, or ethyl.

Embodiment A50

A compound according to any one of the embodiments A1 to A49 wherein Ais thiazolyl, thiadiazolyl, pyrazinyl, pyridyl, benzothiazolyl,5,6-dihydro-4H-cyclopentathiazolyl,4,5,6,7-tetrahydro-benzothiazolo-pyridyl, 6,7-dihydro-pyranothiazolyl,or 4,5,6,7-tetrahydrobenzothiazolyl optionally substituted with one ormore substituents independently selected from R⁷, R⁸ and R⁹.

Embodiment A51

A compound according to embodiment A50 wherein A is

Embodiment A52

A compound according to embodiment A50 wherein A is thiazolyl orthiadiazolyl optionally substituted with one or more substituentsindependently selected from R⁷, R⁸ and R⁹.

Embodiment A53

A compound according to embodiment A52 wherein A is thiazolyl,1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl, optionally substituted withone or more substituents independently selected from R⁷, R⁸ and R⁹.

Embodiment A54

A compound according to embodiment A53 wherein A is

Embodiment A55

A compound according to embodiment A54 wherein A is

Embodiment A56

A compound according to embodiment A55 wherein A is

Embodiment A57

A compound according to any one of the embodiments A1 to A56 wherein R⁷,R⁸ and R⁹ are independently selected from

-   -   halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₁₋₆-alkylamino, C₁₋₆-alkylsulfenyl, —C(O)—O—C₁₋₆-alkyl,        —C(O)—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,        —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl, —NH—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-S—C₁₋₆-alkyl,        C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio each of which is optionally        substituted with one or more substituents independently selected        from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,        aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy,        heteroaryl-thio-C₁₋₆-alkyl, aryloxy, heteroaryloxy,        heteroarylthio, each of which is optionally substituted on the        aryl or heteroaryl part with one or more substituents        independently selected from R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,        C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, each of which is optionally        substituted on the cycloalkyl part with one or more substituents        independently selected from R¹⁸; or    -   C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,        C₃₋₈-heterocyclylthio, or —C(O)—C₃₋₈-heterocyclyl, each of which        is optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,        —C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹, —S(O)₂—R²¹ or        —S(O)₂—NR¹⁹R²⁰, wherein each alkyl part may be substituted with        one or more substituents independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

Embodiment A58

A compound according to embodiment A57 wherein R⁷, R⁸ and R⁹ areindependently selected from

-   -   halogen, carboxy, cyano, or —CF₃; or    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        —C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,        —C₁₋₆-alkoxy-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of        which is optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, each        of which is optionally substituted on the aryl or heteroaryl        part with one or more substituents independently selected from        R¹⁷; or    -   C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of which is        optionally substituted on the cycloalkyl part with one or more        substituents independently selected from R¹⁸; or    -   C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or        —C(O)—C₃₋₈-heterocyclyl, each of which is optionally substituted        with one or more substituents independently selected from R¹⁶;        or    -   —NR¹⁹R²⁰, —C₁₋₆-alkyl-NR¹⁹R²⁰, —S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰,        wherein each alkyl part may be substituted with one or more        substituents independently selected from R²⁵; or    -   —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionally substituted        with one or more substituents independently selected from R²⁶;        or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

Embodiment A59

A compound according to embodiment A58 wherein R⁷, R⁸ and R⁹ areindependently selected from

-   -   halogen, carboxy or —CF₃; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl or        —C(O)—O—C₁₋₆-alkyl, each of which is optionally substituted with        one or more substituents independently selected from R¹⁶; or    -   phenyl, benzyl, or heteroarylthio, wherein heteroaryl is pyridyl        or imidazolyl, and wherein each aryl or heteroaryl is optionally        substituted on the aryl or heteroaryl part with one or more        substituents independently selected from R¹⁷; or    -   cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of        which is optionally substituted on the cycloalkyl part with one        or more substituents independently selected from R¹⁸; or    -   pyrrolidinyl, piperidyl, piperazinyl, or morpholinyl, each of        which is optionally substituted with one or more substituents        independently selected from R¹⁶; or    -   —C(O)NR²²R²³, —S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰; or        two of R⁷, R⁸ and R⁹ can be taken together to form a        C₂₋₅-alkylene bridge.

Embodiment A60

A compound according to embodiment A59 wherein R⁷, R⁸ and R⁹ areindependently selected from halogen, carboxy, —CF₃, —S—CH₃, —S—CH₂CH₃,—S—CH₂CH₂CH₃, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,methoxy, ethoxy, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —CH₂—O—C(O)—CH₃,—CH₂—O—C(O)—CH₂CH₃, —CH₂CH₂—O—C(O)—CH₃, —CH₂CH₂—O—C(O)—CH₂CH₃,—C(O)—O—CH₃, —C(O)—O—CH₂CH₃, each of which is optionally substitutedwith one or more substituents independently selected from R¹⁶; orheteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, eachoptionally substituted on the heteroaryl part with one or moresubstituents independently selected from R¹⁷, or pyrrolidinyl,piperidyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁶, or —S(O)₂—R²¹.

Embodiment A61

A compound according to embodiment A60 wherein R⁷, R⁸ and R⁹ areindependently selected from Cl, F, Br, —CF₃, —S—CH₃, —S—CH₂CH₃,—S—CH₂CH₂CH₃, methyl, ethyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₂CH₃,—C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which is optionally substitutedwith one or more substituents independently selected from R¹⁶; orheteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, eachoptionally substituted on the heteroaryl part with one or moresubstituents independently selected from R¹⁷, or pyrrolidinyl,piperidyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁶.

Embodiment A62

A compound according to any one of the embodiments A1 to A61 whereinR¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen, hydroxy, oxo,carboxy, —CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, —NR¹⁹R²⁰,—C(O)NR¹⁹R²⁰ or —S(O)₂—C₁₋₆-alkyl.

Embodiment A63

A compound according to embodiment A62 wherein R¹⁶, R¹⁷, and R¹⁸ areindependently methyl, ethyl, propyl, halogen, hydroxy, oxo, carboxy,—CF₃, carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl,hydroxy-ethyl, hydroxy-propyl, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃,—C(O)—O—CH₂CH₂CH₃, or —S(O)₂CH₃.

Embodiment A64

A compound according to embodiment A63 wherein R¹⁶, R¹⁷, and R¹⁸ areindependently methyl, ethyl, propyl, halogen, oxo, carboxy,carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl,hydroxy-ethyl, hydroxy-propyl, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃,—C(O)—O—CH₂CH₂CH₃, or —S(O)₂CH₃.

Embodiment A65

A compound according to embodiment A62 wherein R¹⁶, R¹⁷, and R¹⁸ areindependently C₁₋₆-alkyl, carboxy, —NR¹⁹R²⁰, —C(O)—O—C₁₋₆-alkyl or—C(O)NR¹⁹R²⁰.

Embodiment A66

A compound according to any one of the embodiments A1 to A65 wherein R¹⁹and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, naphtyl,C₃₋₈-heterocyclyl, phenyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³or —S(O)₂—C₁₋₆-alkyl, each of which is optionally substituted with oneor more substituents independently selected from R²⁴; or R¹⁹ and R²⁰together with the nitrogen to which they are attached form a 3 to 8membered heterocyclic ring with the said nitrogen atom, the heterocyclicring optionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromR²⁴.

Embodiment A67

A compound according to embodiment A66 wherein R¹⁹ and R²⁰ independentlyrepresent hydrogen, methyl, ethyl, propyl, carboxy-methyl,carboxy-ethyl, carboxy-propyl, hydroxy-methyl, hydroxy-ethyl,hydroxy-propyl, phenyl, phenyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³,or naphtyl, or R¹⁹ and R²⁰ together with the nitrogen to which they areattached form a 3 to 8 membered heterocyclic ring with the said nitrogenatom, the heterocyclic ring optionally containing one or two furtherheteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclicring is optionally substituted with one or more substituentsindependently selected from R²⁴.

Embodiment A68

A compound according to embodiment A66 wherein R¹⁹ and R²⁰ independentlyrepresent hydrogen, C₁₋₆-alkyl, or R¹⁹ and R²⁰ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment A69

A compound according to embodiment A68 wherein R¹⁹ and R²⁰ independentlyrepresent hydrogen, methyl, ethyl, or propyl, or R¹⁹ and R²⁰ togetherwith the nitrogen to which they are attached form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom, wherein the heterocyclicring is pyrrolidyl, piperidyl, piperazinyl, homopiperazinyl, ormorpholinyl, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment A70

A compound according to any one of the embodiments A1 to A69 wherein R²¹is selected from

-   -   C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³ or        hydroxy-C₁₋₆-alkyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

Embodiment A71

A compound according to embodiment A70 wherein R²¹ is selected from

-   -   methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl,        carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl;        or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴; or    -   C₃₋₈-cycloalkyl, or C₃₋₈-cycloalkyl-C₁₋₆-alkyl.

Embodiment A72

A compound according to embodiment A71 wherein R²¹ is selected from

-   -   methyl, ethyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl; or    -   phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein the aryl part is        optionally substituted with one or more substituents        independently selected from R²⁴.

Embodiment A73

A compound according to any one of the embodiments A1 to A72 wherein R²²and R²³ are independently selected from hydrogen, C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,C₃₋₈-cycloalkyl, phenyl, naphtyl, or R²² and R²³ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment A74

A compound according to embodiment A73 wherein R²² and R²³ areindependently selected from hydrogen, methyl, ethyl, propyl, butyl,carboxymethyl, carboxyethyl, carboxypropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphtyl, or R²² and R²³together with the nitrogen to which they are attached form a 3 to 8membered heterocyclic ring with the said nitrogen atom, wherein theheterocyclic ring is pyrrolidyl, piperidyl, piperazinyl,homopiperazinyl, or morpholinyl, the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromR²⁴.

Embodiment A75

A compound according to embodiment A74 wherein R²² and R²³ together withthe nitrogen to which they are attached form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom, wherein the heterocyclicring is pyrrolidyl, piperidyl, piperazinyl, homopiperazinyl, ormorpholinyl, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.

Embodiment A76

A compound according to any one of the embodiments A1 to A75 wherein R²⁴is halogen, hydroxy, carboxy, oxo, —CF₃, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl-aryl, or —S(O)₂R², wherein aryl is phenyl or naphtyl,and heteroaryl is pyridyl or pyrimidyl, and wherein each cyclic moietyis optionally substituted with one or more substituents independentlyselected from R²⁹.

Embodiment A77

A compound according to embodiment A76 wherein R²⁴ is halogen, hydroxy,carboxy, oxo, —CF₃, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or —S(O)₂R²⁸,wherein aryl is phenyl or naphtyl, and heteroaryl is pyridyl orpyrimidyl, and wherein each cyclic moiety is optionally substituted withone or more substituents independently selected from R²⁹.

Embodiment A78

A compound according to embodiment A77 wherein R²⁴ is halogen, carboxy,oxo, —CF₃, C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl,C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or —S(O)₂R², whereinaryl is phenyl or naphtyl, and wherein each cyclic moiety is optionallysubstituted with one or more substituents independently selected fromR²⁹.

Embodiment A79

A compound according to embodiment A78 wherein R²⁴ is carboxy, oxo,C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, aryl,aryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or —S(O)₂R², wherein aryl is phenyl ornaphtyl, and wherein each cyclic moiety is optionally substituted withone or more substituents independently selected from R²⁹.

Embodiment A80

A compound according to any one of the embodiments A1 to A79 wherein R²⁵and R²⁶ are independently C₁₋₆-alkyl, halogen, hydroxy, carboxy, or—CF₃.

Embodiment A81

A compound according to embodiment A80 wherein R²⁵ and R²⁶ areindependently methyl, ethyl, propyl, halogen, hydroxy, carboxy, or —CF₃.

Embodiment A82

A compound according to any one of the embodiments A1 to A81 wherein R²⁸is C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, phenyl, phenyl-C₁₋₆-alkyl,heteroaryl optionally substituted with C₁₋₆-alkyl or —N(CH₃)₂, whereinheteroaryl is imidazolyl, pyridyl or pyrimidyl.

Embodiment A83

A compound according to embodiment A82 wherein R²⁸ is C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, or —N(CH₃)₂.

Embodiment A84

A compound according to any one of the embodiments A1 to A83 wherein R²⁹is halogen, carboxy, —CF₃, C₁₋₆-alkyl, or C₁₋₆-alkoxy.

Embodiment A85

A compound according to any one of the embodiments A1 to A84, whichcompound is an activator of glucokinase, when tested in the GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of 2mM.

Embodiment A86

A compound according to any one of the embodiments A1 to A85, whichcompound is an activator of glucokinase, when tested in the GlucokinaseActivation Assay (I) disclosed herein at a glucose concentration of from10 to 15 mM.

Embodiment A87

A compound according to any one of the embodiments A1 to A86, whichcompound, at a concentration of 30 μM, is capable of providing an atleast 1.5, such as at least 1.7, for instance at least 2.0 foldactivation of glucokinase in the Glucokinase Activation Assay (I)disclosed herein at a glucose concentration of 2 mM.

Embodiment A88

A compound according to any one of the embodiments A1 to A87, whichcompound, at a concentration of 30 μM, is capable of providing an atleast 1.5, such as at least 1.7, for instance at least 2.0 foldactivation of glucokinase in the Glucokinase Activation Assay (I)disclosed herein at a glucose concentration of from 10 to 15 mM.

Embodiment A89

A compound according to any one of the embodiments A1 to A88, which at aconcentration of 5 μM is capable of providing an at least 1.5, such asat least 1.7, for instance at least 2.0 fold activation of glucokinasein the Glucokinase Activation Assay (I) disclosed herein at a glucoseconcentration of 2 mM.

Embodiment A90

A compound according to any one of the embodiments A1 to A89, which at aconcentration of 5 μM is capable of providing an at least 1.5, such asat least 1.7, for instance at least 2.0 fold activation of glucokinasein the Glucokinase Activation Assay (I) disclosed herein at a glucoseconcentration of from 10 to 15 mM.

Embodiment A91

A compound according to any one of the embodiments A1 to A90, whichcompound provides an increase in glucokinase activity, where theincrease in glucokinase activity provided by the compound increases withincreasing concentrations of glucose.

Embodiment A92

A compound according to embodiment A91, which provides an increase inglucokinase activity in Glucokinase Activation Assay (I) disclosedherein at a glucose concentration of 15 mM, which increase issignificantly higher than the increase in glucokinase activity providedby the compound in Glucokinase Activation Assay (I) disclosed herein ata glucose concentration of 5 mM.

Embodiment A93

A compound according to any one of the embodiments A91 to A92, which ata compound concentration of 10 μM provides an increase in glucokinaseactivity in Glucokinase Activation Assay (I) disclosed herein at aglucose concentration of 15 mM, which increase is significantly higherthan the increase in glucokinase activity provided by the compound at acompound concentration of 10 μM in Glucokinase Activation Assay (I)disclosed herein at a glucose concentration of 5 mM.

Embodiment A94

A compound according to any one of the embodiments A91 to A93, which ata compound concentration of 10 μM provides an increase in glucokinaseactivity in Glucokinase Activation Assay (I) disclosed herein at aglucose concentration of 15 mM, which increase is at least 1.1 foldhigher, such as at least 1.2 fold higher, for instance at least 1.3 foldhigher, such as at least 1.4 fold higher, for instance 1.5 fold higher,such as at least 1.6 fold higher, for instance at least 1.7 fold higher,such as at least 1.8 fold higher, for instance at least 1.9 fold higher,such as at least 2.0 fold higher than the increase in glucokinaseactivity provided by the compound at a compound concentration of 10 μMin Glucokinase Activation Assay (I) disclosed herein at a glucoseconcentration of 5 mM.

Embodiment A95

A compound according to any one of the embodiments A1 to A94, whichcompound increases glucose utilization in the liver without inducing anyincrease in insulin secretion in response to glucose.

Embodiment A96

A compound according to any one of the embodiments A1 to A94, whichcompound shows a significantly higher activity in isolated hepatocytescompared to the activity of the compound in Ins-1 cells.

Embodiment A97

A compound according to any one of the embodiments A95 to A96, whichcompound shows a significantly higher activity in isolated hepatocytesmeasured as described in the Glucokinase Activity Assay (II) compared tothe activity of the compound in Ins-1 cells measured as described in theGlucokinase Activity Assay (III).

Embodiment A98

A compound according to embodiment A97, which compound shows an activityin isolated hepatocytes measured as described in the GlucokinaseActivity Assay (II) which activity is at least 1.1 fold higher, such asat least 1.2 fold higher, for instance at least 1.3 fold higher, such asat least 1.4 fold higher, for instance 1.5 fold higher, such as at least1.6 fold higher, for instance at least 1.7 fold higher, such as at least1.8 fold higher, for instance at least 1.9 fold higher, such as at least2.0 fold higher, for instance at least a 3.0 fold higher, such as atleast a 4.0 fold higher, for instance at least 5.0 fold higher, such asat least 10 fold higher than the activity of the compound in Ins-1 cellsmeasured as described in the Glucokinase Activity Assay (III).

Embodiment A99

A compound according to embodiment A97, which compound shows no activityin the Ins-1 cells measured as described in the Glucokinase ActivityAssay (III).

Embodiment A100

A method of preventing hypoglycemia comprising administration of acompound according to any one of the embodiments A1 to 99.

Embodiment A101

The use of a compound according to any one of the embodiments A1 to A99for the preparation of a medicament for the prevention of hypoglycemia.

Embodiment A102

A compound according to any one of embodiments A1 to A99, which is anagent useful for the treatment of an indication selected from the groupconsisting of hyperglycemia, IGT, insulin resistance syndrome, syndromeX, type 2 diabetes, type 1 diabetes, dyslipidemia, hypertension, andobesity.

Embodiment A103

A compound according to any one of embodiments A1 to A102 for use as amedicament.

Embodiment A104

A compound according to any one of embodiments A1 to A102 for treatmentof hyperglycemia, for treatment of IGT, for treatment of Syndrome X, fortreatment of type 2 diabetes, for treatment of type 1 diabetes, fortreatment of dyslipidemia, for treatment of hyperlipidemia, fortreatment of hypertension, for treatment of obesity, for lowering offood intake, for appetite regulation, for regulating feeding behaviour,or for enhancing the secretion of enteroincretins, such as GLP-1.

Embodiment A105

A pharmaceutical composition comprising, as an active ingredient, atleast one compound according to any one of embodiments A1 to A104together with one or more pharmaceutically acceptable carriers orexcipients.

Embodiment A106

A pharmaceutical composition according to embodiment A105 in unit dosageform, comprising from about 0.05 mg to about 1000 mg, preferably fromabout 0.1 mg to about 500 mg and especially preferred from about 0.5 mgto about 200 mg of the compound according to any one of embodiments A1to 104.

Embodiment A107

Use of a compound according to any one of the embodiments A1 to A104 forincreasing the activity of glucokinase.

Embodiment A108

Use of a compound according to any one of embodiments A1 to A104 for thepreparation of a medicament for the treatment of metabolic disorders,for blood glucose lowering, for the treatment of hyperglycemia, for thetreatment of IGT, for the treatment of Syndrome X, for the treatment ofimpaired fasting glucose (IFG), for the treatment of type 2 diabetes,for the treatment of type 1 diabetes, for delaying the progression ofimpaired glucose tolerance (IGT) to type 2 diabetes, for delaying theprogression of non-insulin requiring type 2 diabetes to insulinrequiring type 2 diabetes, for the treatment of dyslipidemia, for thetreatment of hyperlipidemia, for the treatment of hypertension, forlowering of food intake, for appetite regulation, for the treatment ofobesity, for regulating feeding behaviour, or for enhancing thesecretion of enteroincretins.

Embodiment A109

Use of a compound according to any one of embodiments A1 to A104 for thepreparation of a medicament for the adjuvant treatment of type 1diabetes for preventing the onset of diabetic complications.

Embodiment A110

Use of a compound according to any one of embodiments A1 to A104 for thepreparation of a medicament for increasing the number and/or the size ofbeta cells in a mammalian subject, for treatment of beta celldegeneration, in particular apoptosis of beta cells, or for treatment offunctional dyspepsia, in particular irritable bowel syndrome.

Embodiment A111

Use according to any one of the embodiments A108 to A110 in a regimenwhich comprises treatment with a further antidiabetic agent.

Embodiment A112

Use according to any one of the embodiments A108 to A111 in a regimenwhich comprises treatment with a further antihyperlipidemic agent.

Embodiment A113

Use according to any one of embodiments A108 to A112 in a regimen whichcomprises treatment with a further antiobesity agent.

Embodiment A114

Use according to any one of embodiments A108 to A113 in a regimen whichcomprises treatment with a further antihypertensive agent.

Embodiment A115

Use of a compound according to any one of the embodiments A1 to A104 ora pharmaceutical composition according to embodiment A105 or embodimentA106 for the treatment of metabolic disorders, for blood glucoselowering, for the treatment of hyperglycemia, for treatment of IGT, fortreatment of Syndrome X, for the treatment of impaired fasting glucose(IFG), for treatment of type 2 diabetes, for treatment of type 1diabetes, for delaying the progression of impaired glucose tolerance(IGT) to type 2 diabetes, for delaying the progression of non-insulinrequiring type 2 diabetes to insulin requiring type 2 diabetes, fortreatment of dyslipidemia, for treatment of hyperlipidemia, fortreatment of hypertension, for the treatment or prophylaxis of obesity,for lowering of food intake, for appetite regulation, for regulatingfeeding behaviour, or for enhancing the secretion of enteroincretins.

Embodiment A116

Use of a compound according to any one of the embodiments A1 to A104 ora pharmaceutical composition according to embodiment A105 or embodimentA106 for the adjuvant treatment of type 1 diabetes for preventing theonset of diabetic complications.

Embodiment A117

Use of a compound according to any one of the embodiments A1 to A104 ora pharmaceutical composition according to embodiment A105 or embodimentA106 for increasing the number and/or the size of beta cells in amammalian subject, for treatment of beta cell degeneration, inparticular apoptosis of beta cells, or for treatment of functionaldyspepsia, in particular irritable bowel syndrome.

Combination Treatment

In a further aspect of the present invention the present compounds areadministered in combination with one or more further active substancesin any suitable ratios. Such further active agents may be selected fromantidiabetic agents, antihyperlipidemic agents, antiobesity agents,antihypertensive agents and agents for the treatment of complicationsresulting from or associated with diabetes.

Suitable antidiabetic agents include insulin, GLP-1 (glucagon likepeptide-1) derivatives such as those disclosed in WO 98/08871 (NovoNordisk A/S), which is incorporated herein by reference, as well asorally active hypoglycemic agents.

Suitable orally active hypoglycemic agents preferably includeimidazolines, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones, thiazolidinediones, insulin sensitizers,aglucosidase inhibitors, agents acting on the ATP-dependent potassiumchannel of the pancreatic β-cells eg potassium channel openers such asthose disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (NovoNordisk A/S) which are incorporated herein by reference, potassiumchannel openers, such as ormitiglinide, potassium channel blockers suchas nateglinide or BTS-67582, glucagon antagonists such as thosedisclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and AgouronPharmaceuticals, Inc.), all of which are incorporated herein byreference, GLP-1 agonists such as those disclosed in WO 00/42026 (NovoNordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporatedherein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase(protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, GSK-3 (glycogen synthase kinase-3)inhibitors, compounds modifying the lipid metabolism such asantihyperlipidemic agents and antilipidemic agents, compounds loweringfood intake, and PPAR (peroxisome proliferator-activated receptor) andRXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the present invention, the present compounds areadministered in combination with a sulphonylurea eg tolbutamide,chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride,glicazide or glyburide.

In one embodiment of the present invention, the present compounds areadministered in combination with a biguanide eg mefformin.

In one embodiment of the present invention, the present compounds areadministered in combination with a meglitinide eg repaglinide orsenaglinide/nateglinide.

In one embodiment of the present invention, the present compounds areadministered in combination with a thiazolidinedione insulin sensitizereg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone,darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compoundsdisclosed in WO 97/41097 (DRF-2344), WO 97/41119, WO 97/41120, WO00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which areincorporated herein by reference.

In one embodiment of the present invention the present compounds may beadministered in combination with an insulin sensitizer eg such as GI262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544,CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or thecompounds disclosed in WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) andWO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO00/63189 (Novo Nordisk A/S), which are incorporated herein by reference.

In one embodiment of the present invention the present compounds areadministered in combination with an α-glucosidase inhibitor egvoglibose, emiglitate, miglitol or acarbose.

In one embodiment of the present invention the present compounds areadministered in combination with a glycogen phosphorylase inhibitor egthe compounds described in WO 97/09040 (Novo Nordisk A/S).

In one embodiment of the present invention the present compounds areadministered in combination with an agent acting on the ATP-dependentpotassium channel of the pancreatic β-cells eg tolbutamide,glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.

In one embodiment of the present invention the present compounds areadministered in combination with nateglinide.

In one embodiment of the present invention the present compounds areadministered in combination with an antihyperlipidemic agent or aantilipidemic agent eg cholestyramine, colestipol, clofibrate,gemfibrozil, lovastatin, pravastatin, simvastatin, probucol ordextrothyroxine.

Furthermore, the compounds according to the invention may beadministered in combination with one or more antiobesity agents orappetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC3 (melanocortin 3) agonists, MC4 (melanocortin 4)agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF(corticotropin releasing factor) agonists, CRF BP (corticotropinreleasing factor binding protein) antagonists, urocortin agonists, β3adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884,LY377267 or AZ-40140, MSH (melanocytestimulating hormone) agonists, MCH(melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin)agonists, serotonin reuptake inhibitors (fluoxetine, seroxat orcitalopram), serotonin and norepinephrine reuptake inhibitors, 5HT(serotonin) agonists, bombesin agonists, galanin antagonists, growthhormone, growth factors such as prolactin or placental lactogen, growthhormone releasing compounds, TRH (thyreotropin releasing hormone)agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptinagonists, DA (dopamine) agonists (bromocriptin, doprexin),lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR βagonists, adrenergic CNS stimulating agents, AGRP (agouti relatedprotein) inhibitors, H3 histamine antagonists such as those disclosed inWO 00/42023, WO 00/63208 and WO 00/64884, which are incorporated hereinby reference, exendin-4, GLP-1 agonists, ciliary neurotrophic factor,and oxyntomodulin. Further antiobesity agents are bupropion(antidepressant), topiramate (anticonvulsant), ecopipam (dopamine D1/D5antagonist) and naltrexone (opioid antagonist).

In one embodiment of the present invention the antiobesity agent isleptin.

In one embodiment of the present invention the antiobesity agent is aserotonin and norepinephrine reuptake inhibitor eg sibutramine.

In one embodiment of the present invention the antiobesity agent is alipase inhibitor eg orlistat.

In one embodiment of the present invention the antiobesity agent is anadrenergic CNS stimulating agent eg dexamphetamine, amphetamine,phentermine, mazindol phendimetrazine, diethylpropion, fenfluramine ordexfenfluramine.

Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazemand verapamil, and α-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co.,Easton, Pa., 1995.

In one embodiment of the present invention, the present compounds areadministered in combination with insulin, insulin derivatives or insulinanalogues.

In one embodiment of the invention the insulin is an insulin derivativeis selected from the group consisting of B29-N^(ε)-myristoyl-des(B30)human insulin, B29-N^(ε)-palmitoyl-des(B30) human insulin,B29-N^(ε)-myristoyl human insulin, B29-N^(ε)-palmitoyl human insulin,B28-N^(ε)-myristoyl Lys^(B28) Pro^(B29) human insulin,B28-N^(ε)-palmitoyl Lys^(B28) Pro^(B29) human insulin,B30-N^(ε)-myristoyl-Thr^(B29)Lys^(B30) human insulin,B30-N^(ε)-palmitoyl-Thr^(B29)Lys^(B30) human insulin,B29-N^(ε)-(N-palmitoyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N^(ε)-(ω-carboxyheptadecanoyl) human insulin.

In another embodiment of the invention the insulin derivative isB29-N^(ε)-myristoyl-des(B30) human insulin.

In a further embodiment of the invention the insulin is anacid-stabilised insulin. The acid-stabilised insulin may be selectedfrom analogues of human insulin having one of the following amino acidresidue substitutions:

A21G

A21G, B28K, B29P

A21G, B28D

A21G, B28E

A21G, B3K, B29E

A21G, desB27

A21G, B9E

A21G, B9D

A21G, B10E insulin.

In a further embodiment of the invention the insulin is an insulinanalogue. The insulin analogue may be selected from the group consistingof

An analogue wherein position B28 is Asp, Lys, Leu, Val, or Ala andposition B29 is Lys or Pro; and

des(B28-B30), des(B27) or des(B30) human insulin.

In another embodiment the analogue is an analogue of human insulinwherein position B28 is Asp or Lys, and position B29 is Lys or Pro.

In another embodiment the analogue is des(B30) human insulin.

In another embodiment the insulin analogue is an analogue of humaninsulin wherein position B28 is Asp.

In another embodiment the analogue is an analogue wherein position B3 isLys and position B29 is Glu or Asp.

In another embodiment the GLP-1 derivative to be employed in combinationwith a compound of the present invention refers to GLP-1 (1-37),exendin-4 (1-39), insulinotropic fragments thereof, insulinotropicanalogues thereof and insulinotropic derivatives thereof. Insulinotropicfragments of GLP-1 (1-37) are insulinotropic peptides for which theentire sequence can be found in the sequence of GLP-1 (1-37) and whereat least one terminal amino acid has been deleted. Examples ofinsulinotropic fragments of GLP-1 (1-37) are GLP-1 (7-37) wherein theamino acid residues in positions 1-6 of GLP-1 (1-37) have been deleted,and GLP-1 (7-36) where the amino acid residues in position 1-6 and 37 ofGLP-1 (1-37) have been deleted. Examples of insulinotropic fragments ofexendin-4 (1-39) are exendin-4 (1-38) and exendin-4 (1-31). Theinsulinotropic property of a compound may be determined by in vivo or invitro assays well known in the art. For instance, the compound may beadministered to an animal and monitoring the insulin concentration overtime. Insulinotropic analogues of GLP-1 (1-37) and exendin-4 (1-39)refer to the respective molecules wherein one or more of the amino acidsresidues have been exchanged with other amino acid residues and/or fromwhich one or more amino acid residues have been deleted and/or fromwhich one or more amino acid residues have been added with the provisothat said analogue either is insulinotropic or is a prodrug of aninsulinotropic compound. Examples of insulinotropic analogues of GLP-1(1-37) are e.g. Met⁸-GLP-1 (7-37) wherein the alanine in position 8 hasbeen replaced by methionine and the amino acid residues in position 1 to6 have been deleted, and Arg³⁴-GLP-1 (7-37) wherein the valine inposition 34 has been replaced with arginine and the amino acid residuesin position 1 to 6 have been deleted. An example of an insulinotropicanalogue of exendin-4 (1-39) is Ser²Asp³-exendin-4 (1-39) wherein theamino acid residues in position 2 and 3 have been replaced with serineand aspartic acid, respectively (this particular analogue also beingknown in the art as exendin-3). Insulinotropic derivatives of GLP-1(1-37), exendin-4 (1-39) and analogues thereof are what the personskilled in the art considers to be derivatives of these peptides, i.e.having at least one substituent which is not present in the parentpeptide molecule with the proviso that said derivative either isinsulinotropic or is a prodrug of an insulinotropic compound. Examplesof substituents are amides, carbohydrates, alkyl groups and lipophilicsubstituents. Examples of insulinotropic derivatives of GLP-1 (1-37),exendin-4 (1-39) and analogues thereof are GLP-1 (7-36)-amide, Arg³⁴,Lys²⁶(N^(ε)-(γ-Glu(N^(ε)-hexadecanoyl)))-GLP-1 (7-37) andTyr³¹-exendin-4 (1-31)-amide. Further examples of GLP-1(1-37), exendin-4(1-39), insulinotropic fragments thereof, insulinotropic analoguesthereof and insulinotropic derivatives thereof are described in WO98/08871, WO 99/43706, U.S. Pat. No. 5,424,286 and WO 00/09666.

In another aspect of the present invention, the present compounds areadministered in combination with more than one of the above-mentionedcompounds e.g. in combination with metformin and a sulphonylurea such asglyburide; a sulphonylurea and acarbose; nateglinide and mefformin;acarbose and metformin; a sulfonylurea, metformin and troglitazone;insulin and a sulfonylurea; insulin and metformin; insulin, mefforminand a sulfonylurea; insulin and troglitazone; insulin and lovastatin;etc.

It should be understood that any suitable combination of the compoundsaccording to the invention with diet and/or exercise, one or more of theabove-mentioned compounds and optionally one or more other activesubstances are considered to be within the scope of the presentinvention. In one embodiment of the present invention, thepharmaceutical composition according to the present invention comprisese.g. a compound of the invention in combination with metformin and asulphonylurea such as glyburide; a compound of the invention incombination with a sulphonylurea and acarbose; nateglinide andmetformin; acarbose and metformin; a sulfonylurea, mefformin andtroglitazone; insulin and a sulfonylurea; insulin and metformin;insulin, metformin and a sulfonylurea; insulin and troglitazone; insulinand lovastatin; etc.

Pharmaceutical Compositions

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as hard or soft capsules, tablets, troches, dragees, pills,lozenges, powders and granules. Where appropriate, they can be preparedwith coatings such as enteric coatings or they can be formulated so asto provide controlled release of the active ingredient such as sustainedor prolonged release according to methods well known in the art.

Liquid dosage forms for oral administration include solutions,emulsions, aqueous or oily suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and non-aqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Depotinjectable formulations are also contemplated as being within the scopeof the present invention.

Other suitable administration forms include suppositories, sprays,ointments, cremes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, and more preferred from about 0.05 to about 10mg/kg body weight per day administered in one or more dosages such as 1to 3 dosages. The exact dosage will depend upon the frequency and modeof administration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain from 0.05 to about 1000 mg, preferably from about0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200mg. For parenteral routes such as intravenous, intrathecal,intramuscular and similar administration, typically doses are in theorder of about half the dose employed for oral administration. Thecompounds of this invention are generally utilized as the free substanceor as a pharmaceutically acceptable salt thereof. Examples are an acidaddition salt of a compound having the utility of a free base and a baseaddition salt of a compound having the utility of a free acid. The term“pharmaceutically acceptable salts” refers to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid or by reacting theacid with a suitable organic or inorganic base. When a compoundaccording to the present invention contains a free base such salts areprepared in a conventional manner by treating a solution or suspensionof the compound with a chemical equivalent of a pharmaceuticallyacceptable acid. When a compound according to the present inventioncontains a free acid such salts are prepared in a conventional manner bytreating a solution or suspension of the compound with a chemicalequivalent of a pharmaceutically acceptable base. Physiologicallyacceptable salts of a compound with a hydroxy group include the anion ofsaid compound in combination with a suitable cation such as sodium orammonium ion. Other salts which are not pharmaceutically acceptable maybe useful in the preparation of compounds of the present invention andthese form a further aspect of the present invention.

For parenteral administration, solutions of the novel compounds of theformula (I) in sterile aqueous solution, aqueous propylene glycol orsesame or peanut oil may be employed. Such aqueous solutions should besuitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Examplesof solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc,gelatine, agar, pectin, acacia, magnesium stearate, stearic acid andlower alkyl ethers of cellulose. Examples of liquid carriers are syrup,peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines,polyoxyethylene and water. Similarly, the carrier or diluent may includeany sustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax. Thepharmaceutical compositions formed by combining the novel compounds ofthe present invention and the pharmaceutically acceptable carriers arethen readily administered in a variety of dosage forms suitable for thedisclosed routes of administration. The formulations may conveniently bepresented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, incorporated herein by reference, to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present. The pharmaceutical compositions of thepresent invention may also be in the form of oil-in-water emulsions. Theoily phase may be a vegetable oil, for example, olive oil or arachisoil, or a mineral oil, for example a liquid paraffin, or a mixturethereof. Suitable emulsifying agents may be naturally-occurring gums,for example gum acacia or gum tragacanth, naturally-occurringphosphatides, for example soy bean, lecithin, and esters or partialesters derived from fatty acids and hexitol anhydrides, for examplesorbitan monooleate, and condensation products of said partial esterswith ethylene oxide, for example polyoxyethylene sorbitan monooleate.The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectible aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the present invention. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will thus melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the present invention arecontemplated. For the purpose of this application, topical applicationsshall include mouth washes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

In addition, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates are alsoencompassed within the scope of the present invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound according to the present invention, ora pharmaceutically acceptable salt, solvate, or prodrug thereof, and oneor more pharmaceutically acceptable carriers, excipients, or diluents.

If a solid carrier is used for oral administration, the preparation maybe tableted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

A typical tablet that may be prepared by conventional tablettingtechniques may contain:

Core: Active compound (as free compound or salt thereof) 5.0 mg LactosumPh. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite ®IRP88* 1.0 mg Magnesii stearas Ph. Eur. q.s. Coating: Hydroxypropylmethylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg*Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.**Acylated monoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the present invention maycomprise a compound according to the present invention in combinationwith further active substances such as those described in the foregoing.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds offormula (I) along with methods for the preparation of compounds offormula (I). The compounds can be prepared readily according to thefollowing reaction Schemes (in which all variables are as definedbefore, unless so specified) using readily available starting materials,reagents and conventional synthesis procedures. In these reactions, itis also possible to make use of variants which are themselves known tothose of ordinary skill in this art, but are not mentioned in greaterdetail.

The compounds of this invention can be prepared by routes outlined inthe reaction Scheme 1. Reaction of a suitable primary amine (I) with aketone (II) under reductive amination conditions according to methodsknown in the literature affords secondary amine (III). Compound (III)can be converted to the corresponding urea (V) by reaction with, forexample, carbonyl diimidazole and a suitable amino heterocycle (IV)under standard conditions for the synthesis of ureas. For intermediateswhere R¹ or R² contains an additional amino functionality, a suitableprotection group (for example Boc or Cbz) may be employed, allowing fordeprotection and further manipulation (eg. amide coupling, reductiveamination etc) using standard procedures described in the literature.

For intermediates where R¹ or R² contains an additional alcoholfunctionality, a suitable protection group (for example benzyl,tert-butyldimethylsilyl) may be employed, allowing for deprotection andfurther manipulation (eg. ether coupling) using standard proceduresdescribed in the literature.

For intermediates where R¹, R² or A contains an additional carboxyfunctionality, a suitable precursor (eg. alkyl ester) may be employed,allowing for deprotection and further manipulation (eg. acid or basehydrolysis, conversion to amides via reaction with amines) usingstandard procedures described in the literature. Additional manipulationof compound (V) can be performed as described within the generalprocedures outlined within the example section.

EXAMPLES HPLC-MS (Method A)

The following instrumentation is used:

Hewlett Packard series 1100 G1312A Bin Pump

Hewlett Packard series 1100 Column compartment

Hewlett Packard series 1100 G1315A DAD diode array detector

Hewlett Packard series 1100 MSD

Sedere 75 Evaporative Light Scattering detector

The instrument is controlled by HP Chemstation software.

The HPLC pump is connected to two eluent reservoirs containing:

A: 0.01% TFA in water B: 0.01% TFA in acetonitrile

The analysis is performed at 40° C. by injecting an appropriate volumeof the sample (preferably 1 μl) onto the column which is eluted with agradient of acetonitrile.

The HPLC conditions, detector settings and mass spectrometer settingsused are given in the following table.

Column Waters Xterra MS C-18 × 3 mm id 5 μm Gradient 5%-100%acetonitrile linear during 7.5 min at 1.5 mL/min Detection 210 nm(analogue output from DAD) ELS (analogue output from ELS) MS ionisationmode API-ES Scan 100-1000 amu step 0.1 amu

After the DAD the flow is divided yielding approximately 1 mL/min to theELS and 0.5 mL/min to the MS.

NMR

Proton NMR spectra were recorded at ambient temperature using a BruckerAvance DPX 200 (200 MHz), Brucker Avance DPX 300 (300 MHz) and BruckerAvance DPX 400 (400 MHz) with tetramethylsilane as an internal standard.Chemical shifts (δ) are given in ppm

The aminoheterocycle (NH₂A) wherein A is defined as above, can beconverted using standard literature procedures (for example WO2004/002481) to an acyl imidazonium intermediate with carbonyldiimidazole (CDI) in a solvent such as dichloromethane, dichloroethane,tetrahydrofuran, or DMF. Treatment with R¹R²NH, wherein R¹ and R² are asdefined above, gives the compound of formula (I). The aminoheterocycle(NH₂A) or secondary amine (R¹R²NH) can be either commercially availablecompounds or compounds that can be prepared following proceduresdescribed in the literature or prepared as described in the relevantexample and general procedures.

General Procedure (B)

The desired amines R¹R²NH described in General procedure (A), wherein R¹and R² are as defined above are commercially available, or can beprepared by a reductive amination with a suitable primary amine and aketone as shown below, following procedures described in the literature(Org. Prep. Proced. Int. 1979, 11, 201).

General Procedure (C)

Preparation of 1,1-dicycloalkyl-3-heteroaryl-urea

A mixture of 1,1′-carbonyldiimidazole (98 mg, 0.6 mmol), aminoheteroaryl compound (0.6 mmol) and 4-(N,N-dimethylamino)pyridine (5 mg)in dichloroethane (5 ml) was heated at 80° C. for 1 h. The reactionmixture was cooled to room temperature and was added solution of adicycloalkylamine (0.5 mmol) in dichloroethane (2 ml). The resultingsuspension was heated at 80° C. for 3 h and concentrated. The residuewas purified by column chromatography (silica, CH₂Cl₂ then 5-10% ethylacetate in CH₂Cl₂) to afford the desired urea 50-60% yield.

General Procedure (D)

Synthesis of 1,1-dicycloalkyl-3-(5-thiaalkyl-thiazol-2-yl)ureas

Hal=HalogenR¹ and R², A and R¹⁷ as defined in compound claims

Representative Example

A mixture of 3-(5-bromo-thiazol-2-yl)-1,1-dicycloalkylurea (Example 49)(1 mmol), alkylthiol (2 mmol) and DIEA (2 mmol) in DMF (5 mL) was heatedat 80° C. for 3 h. The mixture was poured into water (20 mL) and wasextracted with ethyl acetate (3×25 mL). The organic layer was washedwith water (2×30 mL), brine (1×30 mL), dried (anhydrous Na₂SO₄) andconcentrated in vacuo to furnish a residue containing3-(5-alkylthio-thiazol-2-yl)-1,1-dicyclohexyl-urea. The crude productwas purified by column chromatography (silica, CH₂Cl₂ then 5-20% ethylacetate in CH₂Cl₂) to afford3-(5-alkylthio-thiazol-2-yl)-1,1-dicyclohexyl-urea in 35-45% yield.

General Procedure (E)

Synthesis of 1,1-dicycloalkyl-3-(5-thiaheteroaryl-thiazol-2-yl)ureas

A mixture of arylthiol (2 mmol) and tert.BuOK (2 mmol) in DMF (5 mL) wasstirred for 15 min. To this solution was added3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea (Example 49) (1 mmol) andwas heated at 80° C. for 3 h. The mixture was poured into water (20 mL)and was extracted with ethyl acetate (3×25 mL). The organic layer waswashed with water (2×30 mL), brine (1×30 mL), dried (anhydrous Na₂SO₄)and concentrated in vacuo to furnish a residue containing(5-arylthio-2-thiazolyl)-1,1-dicyclohexyl-urea. The crude product waspurified by column chromatography (silica, CH₂Cl₂ then 5-20% ethylacetate in CH₂Cl₂ and 2% MeOH in CH₂Cl₂) to afford the desired urea in25-45% yield.

General Procedure (F)

Hydrolysis of Esters

Ester (1 mmol) was dissolved in 1:1 mixture of THF and methanol (5 mL).To this solution was added 2 M solution of LiOH (2 mL, 4 mmol). Themixture was stirred for 4-6 h and was concentrated. The residue wasdiluted with water (10 mL) and the aqueous layer was washed with ethylacetate (2×10 mL). The water layer was acidified with HCl to pH 6.0 andthe precipitated acid was extracted with ethyl acetate (2×50 mL). Theorganic layer was washed with water (2×20 mL), dried (Na₂SO₄) andconcentrated in vacuo to furnish corresponding carboxylic acid in almostquantitative yield.

General Procedure (G)

Synthesis of Acyl- or Sulfonyl-piperidinyl-(thiazolyl)-cycloalkyl ureas.

Step 1. To N-Boc-piperidone (10 g) in a mixture of MeOH (50 ml) and THF(50 ml) is added an equimolar amount of cycloalkylamine (4.5 g) at roomtemperature. Sodium cyanoborohydride (6.3 g, 2 eq) is added and thereaction stirred at room temperature overnight. The crude product isfiltered through celite, concentrated in vacuo, redissolved/suspended inether, stirred for 1 h, and decanted. This procedure is repeated 4 timesand the combined ether-phases are concentrated in vacuo to afford4-cycloalkylamino-piperidine-1-carboxylic acid tert-butyl ester as apale yellow oil which is used directly in step 2.

Step 2. A equimolar mixture of 1,1-carbonyldiimidazole, aminoheteroarylcompound (for example 5-methylaminothiazole) and DMAP (5 mol %) indichloroethane is heated for 4 h at 80° C. then cooled to roomtemperature. The amine product (1 equivalent) from Step 1 is added andthe reaction is stirred overnight. Work up and chromatography (5% ethylacetate in hexane) affords the desired Boc protected urea.

Step 3. Boc deprotection is performed using trifluoroacetic acid in DCMfor 2 h at room temperature. Excess TFA and DCM are removed in vacuo togive the crude amine which is used directly in the next Step.

Step 4. Acylation with either an HOBt activated carboxylic acid or asulfonylchloride affords the required amide or sulfonamide respectivelyvia established literature procedures.

Step 5. If the substituent on the aminoheteroaryl moiety contains anester functionality this can be hydrolysed using lithium hydroxide inmethanol to give the corresponding acid.

General Procedure (H)

Synthesis of 5-thioalkyl/5-thioalkylamino substituted thiazolyl ureas.

Step 1. A equimolar mixture of 1,1-carbonyldiimidazole, the appropriate5-thiocyanato-thiazol-2-ylamine (commercially available or prepared asdescribed in J. Am. Chem. Soc 71, 4007, 1949 or J. Med. Chem., 20, 572,1977) and DMAP (5 mol %) in THF is heated for 2 h at 60-70° C. and thencooled to room temperature. The secondary amine (1 equivalent; preparedas described in General procedure (C) or General Procedure (I) is addedand the reaction is stirred overnight at room temperature. The reactionmixture was quenched with water and organic phase was isolated. Theaqueous phase was extracted with CH₂Cl₂, and the combined organic phaseswere dried and concentrated in vacuo. The crude product was purified byflash chromatography (heptane: CH₂Cl₂ 20:80→0:100 or heptane:CH₂Cl₂:EtOAc 20:80:0→0:0:100) afforded the desired(5-thiocyanato-thiazol-2-yl)urea.

Step 2. An equimolar mixture of 1,4-dithiothreitol (DTT) and theappropriate (5-thiocyanato-thiazol-2-yl)urea (prepared as described inStep 1) in MeOH (4 mL/mmol) was stirred in a nitrogen atmosphere at roomtemperature for 2 h. Addition of K₂CO₃ (3 equiv) and the appropriatealkyl halide (1-3 equivalents). The reaction mixture was stirred at roomtemperature over night and quenched with water. Addition of CH₂Cl₂. Theorganic phase was isolated and the aqueous phase was extracted withCH₂Cl₂, and the combined organic phases were concentrated in vacuo. Thecrude product was dissolved in MeOH or MeCN and purified by reversephase preparative HPLC (Gilson) to give the desired product.

General Procedure (I)

Synthesis of N-acylated cycloalkyl-cycloalkylamino-amines.

Step 1. A equimolar mixture of 4-piperidone monohydrate hydrochloride,diisopropylethylamine and the appropriate acyl chloride in CH₂Cl₂ (1mL/mmol) was stirred at room temperature overnight. The reaction mixturewas added to CH₂Cl₂ and the organic phase was washed with 1N NaOH(twice), 1N HCl and brine and subsequently concentrated in vacuo to givethe acylated piperidone which was used directly in Step 2.

Step 2. A equimolar mixture the acylated piperidone (prepared in Step 1)and the appropriate cycloalkylamine in THF:MeOH (1:1, 2 mL/mmol) and 3 Åmolsieves was added sodium cyanoborohydride (2 equiv) and the mixturewas stirred at room temperature overnight to give the crude secondaryamine which is filtered through celite, concentrated in vacuo,redissolved/suspended in ether, stirred for 1 h, and decanted. Theprocedure is repeated 4 times and the combined ether-phases areconcentrated in vacuo to afford the desired N-acylatedcycloalkylpiperidin-4-yl amine.

General Procedure (J) for the Synthesis of Alkyl/Arylsulfones:

Aryl/alkyl-sulfanyl derivative of dialkyl-thiazolyl urea (0.5 mmol) wasdissolved in CH₂Cl₂ (6 mL) and was cooled to 0° C. in an ice bath. Tothis solution was added peroxy acetic acid (10 mmol) in CH₂Cl₂ (5 mL).The mixture was stirred for 4 h at 0° C. and was diluted with CH₂Cl₂ (50mL). The organic layer was washed with saturated solution of NaHCO₃(2×30 mL), water (3×30 mL), brine (1×30 mL), dried (anhydrous Na₂SO₄)and concentrated in vacuo. The crude mixture was purified by columnchromatography with CH₂Cl₂ then 5-20% ethyl acetate in CH₂Cl₂ to givethe corresponding sulfone.

General Procedure (K) for the Synthesis of Amides.

A solution of 2-(3,3-dicycloalkylureido)-thiazole-4-carboxylic acid or2-(3,3-dicycloalkylureido)-thiazole-5-carboxylic acid (0.60 mmol), DIEA(0.25 mL, 1.50 mmol) and TFFH (270 mg, 0.6 mmol) in THF (5 mL) wasstirred for 30 min. To this mixture was added amine or amino acid-ester(0.6 mmol) and the reaction mixtures was stirred for 12 h at rt. Thereaction mixture was concentrated and purified by flash chromatographyusing CH₂Cl₂ and ethyl acetate (4:1) to afford the corresponding amide.

General Procedure (L) for the Synthesis of Alkyl/Aryl-Thiazolyl Ureas

To a solution of 1,1-dicycloalkyl-3-(4-hydroxymethyl-thiazol-2-yl)urea(1 mmol) in DCM (5 mL) was added PBr₃ (1.2 mmol) at 0° C. and stirredfor 2 h. The mixture was slowly quenched with ice water and wasextracted with DCM (3×20 mL). The organic layer was washed with water(2×20 mL), brine (1×20 mL), dried over sodium sulfate and concentratedto afford 1,1-dicycloalkyl-3-(4-bromomethyl-thiazol-2-yl)urea. Thiscrude bromide was used as such for the next step.

A mixture of aryl thiol (2 mmol) and potassium tert-butoxide (2 mmol) inDMF (5 mL) was stirred for 15 min. To this solution was added1,1-dicycloalkyl-3-(4-bromomethyl-thiazol-2-yl)urea (1 mmol) and washeated at 80° C. for 3 h. The mixture was poured into water (20 mL) andwas extracted with ethyl acetate (3×25 mL). The organic layer was washedwith water (2×30 mL), brine (1×30 mL), dried (anhydrous Na₂SO₄) andconcentrated in vacuo to furnish a residue containingaryl/alkyl-thiazolyl urea. The crude product was purified by columnchromatography (silica, CH₂Cl₂ then 5-20% ethyl acetate in CH₂Cl₂ and 2%MeOH in CH₂Cl₂) to afford the desired urea.

General Procedure (M) for the Removal of Boc-Group to Form AmineHydrochlorides

To the Boc-protected amine (0.5 mmol) was added 4 M solution of HCl indioxane (2 mL). The mixture was stirred for 30 min. The mixture wasconcentrated and the residue was washed with anhydrous ether andconcentrated to get amine hydrochloride in almost quantitative yield.

General Procedure (N) for the Acylation of Amines

A solution of amine/amine hydrochloride (0.5 mmol) in DCM was cooled to0° C. To this solution was added acyl chloride (0.6 mmol) followed byDIEA (1.5 mmol). The mixture was stirred for 2 h and concentrated. Theresidue was purified by column chromatography (silica, CH₂Cl₂ then 5-20%ethyl acetate in CH₂Cl₂ and 2% MeOH in CH₂Cl₂) to afford the desiredproduct.

General Procedure (P) for Reductive Amination

To a mixture of 1,1-dialkyl-3-(5-formyl-thiazol-2-yl)-urea (0.30 mmol)and dry powdered molecular sieves in CH₂Cl₂ (2 mL) was added theappropriate alkyl-amino hydrochloride (0.36 mmol). The mixture wasstirred for 20 minutes. To this was added sodium triacetoxyborohydride(0.39 mmol) and the reaction was stirred for six to 12 hours at ambienttemperature. The reaction was quenched with saturated aqueous Na₂HCO₃(10 mL), extracted once with CH₂Cl₂ (10 mL) and once with ethyl acetate(10 mL). The combined organic extractions were dried over MgSO₄. Afterconcentration to a crude oil, the desired thiazole urea was purified bycolumn chromatography (silica gel and 5% ethyl acetate in CH₂Cl₂, then1% MeOH and 10% ethyl acetate in CH₂Cl₂ followed by 2% MeOH and 10%ethyl acetate in CH₂Cl₂) to afford the product in 14 to 65% yield.

General Procedure (Q) for the Preparation of Sulfonamides

Amine hydrochloride (0.20 mmol) and diisopropyl ethylamine (DIEA, 0.40mmol) were combined in CH₂Cl₂ (3 mL) and stirred at ambient temperature.The desired sulfonyl chloride (0.30 mmol) was added and the reaction wasstirred until complete (15-45 minutes). The volatile components wereremoved with reduced pressure and the residue was purified by columnchromatography (silica gel and 5% ethyl acetate in CH₂Cl₂, then 1% MeOHand 10% ethyl acetate in CH₂Cl₂) to afford the product in 44 to 87%yield.

Example 1 1,1-Dicyclohexyl-3-thiazol-2-yl-urea

To a solution of aminothiazole (50 mg, 0.5 mmol) in dichloromethane wasadded carbonyldiimidazole (81 mg, 0.5 mmol) and the solution stirred 2 hat room temperature. Dicyclohexylamine (1 eq) was then added and thereaction stirred overnight at room temperature. The reaction mixture isthen diluted with ethyl acetate (8 mL), washed successively with 10%sodiumhydrogensulphate (3 mL), water (3 mL), dried over magnesiumsulphate, concentrated in vacuo, and the residue purified by HPLC(Gilson 1, X-terra column; 0-100% CH₃CN/H₂O/0, 1% TFA; 15 min; flow 50ml/min) to give the title product (52 mg).

¹H NMR (DMSO-d₆): δ 7.28-7.35 (1H, m), 6.91-6.98 (1H, m), 3.35-3.60 (2H,m), 1.01-2.11 (20H, m); HPLC-MS (Method A): m/z=308 (M+1); R_(t)=4.07min.

Example 2 3-(5-Chloro-thiazol-2-yl)-1,1-dicyclohexyl-urea

Prepared as described in general procedure (A) using5-chloro-2-aminothiazole and dicyclohexylamine.

¹H NMR (CDCl₃): δ 8.20 (1H, bs), 7.15 (1H, s), 3.30-3.50 (2H, m),0.80-2.00 (20H, m); HPLC-MS (Method A): m/z=342.1 (M+); Rt=5.41 min.

Example 3 1,1-Dicyclohexyl-3-(4-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (A) using4-methyl-2-aminothiazole and dicyclohexylamine.

¹H NMR (CDCl₃): δ 8.10 (1H, bs), 6.40 (1H, s), 3.35-3.55 (2H, m),1.60-1.96 (14H, m), 1.05-1.50 (6H, m); HPLC-MS (Method A): m/z=322.2(M+1); R_(t)=4.42 min.

Example 4 1,1-Dicyclohexyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (A) using5-methyl-2-aminothiazole and dicyclohexylamine.

¹H NMR (CDCl₃): δ 7.93 (1H, bs), 6.92 (1H, s), 3.39-3.51 (2H, m),1.58-1.92 (14H, m), 1.05-1.45 (6H, m); HPLC-MS (Method A): m/z=322(M+1); R_(t)=4.22 min.

Example 5 1,1-Dicyclohexyl-3-(5-methyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure (A) using5-methyl-2-amino-1,3,4-thiadiazole and dicyclohexylamine.

¹H NMR (CDCl₃): δ 8.31 (1H, bs), 3.35-3.55 (2H, m), 2.63 (3H, s),1.55-1.95 (14H, m), 1.09-1.45 (6H, m); HPLC-MS (Method A): m/z=323.2(M+1); R_(t)=4.46 min.

Example 6 2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazole-5-carboxylicacid ethyl ester

Prepared as described in general procedure (A) using4-methyl-5-carboxyethyl-2-aminothiazole and dicyclohexylamine.

¹H NMR (CDCl₃): δ 8.05 (1H, bs), 4.25 (2H, q), 3.31-3.49 (2H, m), 2.55(3H, s), 1.55-1.95 (14H, m), 1.11-1.45 (9H, m); HPLC-MS (Method A):m/z=394.2 (M+); R_(t)=5.61 min.

Example 71-(4-Methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and (4-methyl-cyclohexyl)-(tetrahydro-pyran-4-yl)-amine.

HPLC-MS (Method A): m/z=324 (M+1); R_(t)=3.36 min.

Example 81-(4-tert-Butyl-cyclohexyl)-3-(5-chloro-thiazol-2-yl)-1-cyclopentyl-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and (4-tert-butyl-cyclohexyl)-cyclopentyl-amine

HPLC-MS (Method A): m/z=384 (M+); R_(t)=6.28 min.

Example 9 1-Cyclopentyl-1-(4-isopropyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and (4-isopropyl-cyclohexyl)-cyclopentyl-amine

HPLC-MS (Method A): m/z=336 (M+); R_(t)=4.97 min.

Example 101-Bicyclo[2.2.1]hept-2-yl-3-(5-chloro-thiazol-2-yl)-1-cyclopentyl-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and bicyclo[2.2.1]hept-2-yl-cyclopentyl-amine

HPLC-MS (Method A): m/z=340 (M+); R_(t)=5.48 min.

Example 111-(3,5-Dimethyl-cyclohexyl)-1-(4-methyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and (3,5-dimethyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=350 (M+); R_(t)=5.13 min.

Example 12 4-(1-Cyclopentyl-3-thiazol-2-yl-ureido)-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) usingaminothiazole and 4-cyclopentylamino-cyclohexanecarboxylic acid ethylester.

HPLC-MS (Method A): m/z=366 (M+1); R_(t)=3.84 min.

Example 133-(5-Chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(4-trifluoromethyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(4-methyl-cyclohexyl)-(4-trifluoromethyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=424 (M+1); R_(t)=5.41 min.

Example 143-(5-Chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(4-methyl-cyclohexyl)-(tetrahydro-pyran-4-yl)-amine.

HPLC-MS (Method A): m/z=358 (M+); R_(t)=4.64 min.

Example 153-(5-Chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-thiopyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(4-methyl-cyclohexyl)-(tetrahydro-thiopyran-4-yl)-amine.

HPLC-MS (Method A): m/z=374 (M+); R_(t)=4.91 min.

Example 163-(5-Chloro-thiazol-2-yl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=414 (M+); R_(t)=4.70 min.

Example 17 3-(5-Chloro-thiazol-2-yl)-1,1-bis-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and bis-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=370 (M+); R_(t)=5.78 min.

Example 183-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and cyclopentyl-(4-methyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=342 (M+1); R_(t)=5.59 min.

Example 191-(4-Methyl-cyclohexyl)-3-thiazol-2-yl-1-(4-trifluoromethyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(4-methyl-cyclohexyl)-(4-trifluoromethyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=390 (M+1); R_(t)=4.67 min.

Example 20 3-(5-Chloro-thiazol-2-yl)-1,1-dicyclopentyl-urea

Prepared as described in general procedure (A) using5-chloro-2-aminothiazole and dicyclopentylamine.

HPLC-MS (Method A): m/z=314 (M+); R_(t)=5.03 min.

Example 213-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(tetrahydro-thiopyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole andcyclopentyl-(tetrahydro-thiopyran-4-yl)-amine.

HPLC-MS (Method A): m/z=346 (M+1); R_(t)=4.82 min.

Example 223-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and cyclopentyl-(tetrahydro-pyran-4-yl)-amine.

HPLC-MS (Method A): m/z=330 (M+); R_(t)=4.09 min.

Example 23 1,1-Bis-(4-methyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and bis-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=336 (M+1); R_(t)=4.88 min.

Example 244-[3-(5-Chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and4-(4-methyl-cyclohexylamino)-cyclohexanecarboxylic acid ethyl ester

HPLC-MS (Method A): m/z=429 (M+1); R_(t)=5.21 min.

Example 251-(4-tert-Butyl-cyclohexyl)-1-(4-methyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(4-tert-butyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=378 (M+1); R_(t)=5.84 min.

Example 264-[3-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-ureido]-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and 4-Cyclopentylamino-cyclohexanecarboxylicacid ethyl ester.

HPLC-MS (Method A): m/z=400 (M+); R_(t)=5.08 min.

Example 271-(4-Isopropyl-cyclohexyl)-1-(4-methyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and (4-isopropyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=364 (M+1); R_(t)=5.52 min.

Example 281-Bicyclo[2.2.1]hept-2-yl-3-(5-chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole andbicyclo[2.2.1]hept-2-yl-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=368 (M+); R_(t)=5.95 min.

Example 293-(5-Chloro-thiazol-2-yl)-1-(4-isopropyl-cyclohexyl)-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(4-isopropyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=399 (M+1); R_(t)=6.19 min.

Example 303-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole andcyclopentyl-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine

HPLC-MS (Method A): m/z=386 (M+); R_(t)=4.55 min.

Example 31 1-Cyclopentyl-1-(4-methyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and cyclopentyl-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=308 (M+1); R_(t)=4.25 min.

Example 321-(4-Methyl-cyclohexyl)-1-(tetrahydro-thiopyran-4-yl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and(4-methyl-cyclohexyl)-(tetrahydro-thiopyran-4-yl)-amine.

HPLC-MS (Method A): m/z=340 (M+1); R_(t)=4.04 min.

Example 333-(5-Chloro-thiazol-2-yl)-1-(3,5-dimethyl-cyclohexyl)-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(3,5-dimethyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=385 (M+1); R_(t)=6.00 min.

Example 344-[1-(4-Methyl-cyclohexyl)-3-thiazol-2-yl-ureido]-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) usingaminothiazole and 4-(4-methyl-cyclohexylamino)-cyclohexanecarboxylicacid ethyl ester

HPLC-MS (Method A): m/z=394 (M+1); R_(t)=4.43 min.

Example 353-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(3,5-dimethyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(3,5-dimethyl-cyclohexyl)-(4-methyl-cyclopentyl)-amine.

HPLC-MS (Method A): m/z=356 (M+1); R_(t)=5.86 min.

Example 361-(4-tert-Butyl-cyclohexyl)-3-(5-chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and(4-tert-butyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=412 (M+1); R_(t)=6.44 min.

Example 373-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(4-isopropyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and (4-tert-butyl-cyclohexyl)-cyclopentyl-amine

HPLC-MS (Method A): m/z=370 (M+1); R_(t)=6.20 min.

Example 381-(4-Methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and(4-methyl-cyclohexyl)-(tetrahydro-pyran-4-yl)-amine.

HPLC-MS (Method A): m/z=338 (M+1); R_(t)=3.50 min.

Example 391-(4-Methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-1-(tetrahydro-thiopyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and(4-methyl-cyclohexyl)-(tetrahydro-thiopyran-4-yl)-amine.

HPLC-MS (Method A): m/z=354 (M+1); R_(t)=4.15 min.

Example 401-(4-tert-Butyl-cyclohexyl)-1-(4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and(4-tert-butyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=392 (M+1); R_(t)=5.81 min.

Example 414-[1-(4-Methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-ureido]-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and4-(4-methyl-cyclohexylamino)-cyclohexanecarboxylic acid ethyl ester.

HPLC-MS (Method A): m/z=408 (M+1); R_(t)=4.44 min.

Example 421-(2,3-Dioxa-spiro[4.5]dec-8-yl)-1-(4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and(1,4-Dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=3.94 (M+1); R_(t)=3.88 min.

Example 431-(4-Isopropyl-cyclohexyl)-1-(4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and(4-tert-butyl-cyclohexyl)-(4-methyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=378 (M+1); R_(t)=5.57 min.

Example 441-(4-Methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and(4-methyl-cyclohexyl)-(4-trifluoromethyl-cyclohexyl)-amine

HPLC-MS (Method A): m/z=404 (M+1); R_(t)=4.81 min.

Example 45 1,1-Bis-(4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and bis-(4-methyl-cyclohexyl)-amine.

HPLC-MS (Method A): m/z=350 (M+1); R_(t)=4.89 min.

Example 46 [5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-yl]-aceticacid ethyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino[1,3,4]thiadiazol-2-yl]-5-acetic acid ethyl ester.

HPLC-MS (Method A): m/z=395 (M+1); R_(t)=4.37 min.

Example 472-(3,3-Dicyclohexyl-ureido)-4,5,6,7-tetrahydro-benzothiazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethylester (prepared as described in Tet. Lett. 2001, 8911)

HPLC-MS (Method A): m/z=435 (M+1); R_(t)=4.81 min.

Example 48 1,1-Dicyclohexyl-3-(3-methyl-[1,2,4]thiadiazol-5-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 3-methyl-5-amino-[1,2,4]thiadiazole

HPLC-MS (Method A): m/z=323 (M+1); R_(t)=4.24 min.

Example 49 3-(5-Bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea

Prepared as described in general procedure (C) using dicyclohexylamineand 2-amino-5-bromothiazole.

¹H NMR (CDCl₃): δ 0.80-2.00 (m, 20H), 3.38 (m, 2H), 7.23 (s, 1H), 8.18(br, 1H); HPLC-MS m/z=387 (M+1).

Example 50 2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid methylester

Prepared as described in general procedure (C) using dicyclohexylamineand 2-aminothiazole-5-carboxylic acid methyl ester.

¹H NMR (CDCl₃): δ 1.02-1.90 (m, 20H), 3.41 (m, 2H), 3.84 (s, 3H), 8.02(s, 1H), 8.08 (br, 1H); HPLC-MS: m/z=366 (M+1).

Example 51 2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid

Prepared as described in general procedure (F) from2-(3,3-dicyclohexyl-ureido)-thiazole-5-carboxylic acid methyl ester.

¹H NMR (DMSO-d₆): δ 1.02-1.87 (m, 20H), 3.42 (m, 2H), 7.92 (s, 1H),11.02 (br, 1H); HPLC-MS: m/z=352 (M+1).

Example 521,1-Dicyclohexyl-3-(5-methylsulfanyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure {circle around (C)} usingdicyclohexylamine and 2-amino-5-methylsulfanyl-1,3,4-thiadiazole.

¹H NMR (CDCl₃): δ 1.12-1.32 (m, 6H), 1.61-1.88 (m, 14H), 2.66 (s, 3H),3.39 (m, 2H), 9.02 (br, 1H); HPLC-MS: m/z=355 (M+1).

Example 531,1-Dicyclohexyl-3-(5-methanesulfonyl-[1,3,4]thiadiazol-2-yl)-urea

1,1-Dicyclohexyl-3-(5-methanesulfanyl-[1,3,4]thiadiazol-2-yl)-urea (0.5mmol) was dissolved in CH₂Cl₂ (6 mL) and was cooled to 0° C. in an icebath. To this solution was added peracetic acid (10 mmol) in CH₂Cl₂ (5mL). The mixture was stirred for 4 h at 0° C. and was diluted withCH₂Cl₂ (50 mL). The organic layer was washed with saturated solution ofNaHCO₃ (2×30 mL), water (3×30 mL), brine (1×30 mL), dried (anhydrousNa₂SO₄) and concentrated in vacuo. The crude mixture was purified bycolumn chromatography with CH₂Cl₂ then 5-20% ethyl acetate in CH₂Cl₂ togive 1,1-dicyclohexyl-3-(5-methanesulfonyl-[1,3,4]thiadiazol-2-yl)-urea(155 mg).

¹H NMR (CDCl₃): δ 1.17-1.35 (m, 6H), 1.64-1.85 (m, 14H), 3.32 (s, 3H),3.41 (m, 2H), 9.33 (br, 1H); HPLC-MS: m/z=387 (M+1).

Example 54 [2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and methyl thioglycolate

¹H NMR (CDCl₃): δ 1.14-1.36 (m, 6H), 1.60-1.86 (m, 14H), 3.42 (m, 4H),3.71 s, 3H), 7.40 (s, 1H), 7.86 (br, 1H); HPLC-MS: m/z=412 (M+1).

Example 55 [2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid

Prepared as described in general procedure (F) from[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid methylester.

¹H NMR (DMSO-d₆): δ 1.12-1.96 (m, 20H), 3.38 (m, 2H), 3.45 s, 2H), 7.34(s, 1H), 11.6 (br, 1H); HPLC-MS: m/z=398 (M+1).

Example 561,1-Dicyclohexyl-3-[5-(pyridin-2-ylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 2-mercaptopyridine.

HPLC-MS: m/z=417 (M+1).

Example 572-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-1H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea andethyl-2-mercapto-1H-imidazole-4-carboxylate.

¹H NMR (CDCl₃): δ 1.09 (t, 3H), 1.23-1.33 (m, 6H), 1.60-1.82 (m, 14H),3.34 (m, 4H), 4.29 (q, 2H), 7.50 (s, 1H), 7.64 (s, 1H), 7.89 (br, 1H),7.94 (br, 1H); HPLC-MS: m/z=478 (M+1).

Example 582-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-1H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-1H-imidazole-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₆): δ 1.04-1.96 (m, 20H), 3.40 (m, 2H), 7.56 (s, 2H), 7.79(br, 1H), 11.2 (br, 1H); HPLC-MS: m/z=450 (M+1).

Example 592-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea andethyl-2-mercapto-1-methyl-1H-imidazole-4-carboxylate.

¹H NMR (CDCl₃): δ 1.16 (t, 3H), 1.29-1.34 (m, 6H), 1.68-1.84 (m, 14H),3.38 (m, 4H), 3.97 (s, 3H), 4.29 (q, 2H), 7.55 (s, 1H), 7.67 (s, 1H),7.93 (br, 1H); HPLC-MS: m/z=492 (M+1).

Example 602-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-3-methyl-3H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₆): δ 1.17-1.89 (m, 20H), 3.38 (m, 2H), 3.88 (s, 3H), 7.57(s, 1H), 7.61 (s, 1H); HPLC-MS: m/z=464 (M+1).

Example 611,1-Dicyclohexyl-3-[5-(1-methyl-1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and2-mercapto-1-methyl-1H-imidazole.

¹H NMR (CDCl₃): δ 1.09-1.31 (m, 6H), 1.64-1.80 (m, 14H), 3.35 (m, 4H),3.73 (s, 3H), 6.88 (d, 1H), 6.99 (d, 1H), 7.47 (s, 1H), 8.14 (br, 1H);HPLC-MS: m/z=420 (M+1).

Example 62 1,1-Dicyclohexyl-3-pyrazin-2-yl-urea

Prepared as described in general procedure (C), using dicyclohexylamineand 2-aminopyrazine.

¹H NMR (CDCl₃): δ 1.15-1.36 (m, 6H), 1.65-1.86 (m, 14H), 3.49 (m, 2H),6.99 (br, 1H), 8.12 (d, 1H), 8.19 (d, 1H), 9.33 (s, 1H); HPLC-MS:m/z=303 (M+1).

Example 63 2-(3,3-Dicyclohexyl-ureido)-thiazole-4-carboxylic acid ethylester

Prepared as described in general procedure (C) using dicyclohexylamineand ethyl-2-amino-4-thiazolecarboxylate.

¹H NMR (CDCl₃): δ 8.12 (1H, s), 4.21 (3H, q), 3.30-3.45 (2H, m),1.25-1.90 (23H, m); HPLC-MS: m/z=380 (M+1).

Example 64 2-(3,3-Dicyclohexyl-ureido)-thiazole-4-carboxylic acid

Prepared as described in the general procedure (F) from2-(3,3-dicyclohexyl-ureido)-thiazole-4-carboxylic acid ethyl ester.

¹H NMR (CDCl₃): δ 11.41 (1H, s), 7.92 (1H, s), 3.95 (2H, m), 1.15-1.90(20H, m); HPLC-MS: m/z=352 (M+1).

Example 65 Acetic acid 2-(3,3-dicyclohexyl-ureido)-thiazol-4-ylmethylester

Prepared as described in general procedure (C) using dicyclohexylamineand acetic acid-2-aminothiazol-4-yl methyl ester.

¹H NMR (CDCl₃): δ 7.95 (1H, s), 6.81 (1H, s), 5.05 (2H, s), 3.40 (2H,m), 2.12 (3H, s), 1.15-1.90 (20H, m); HPLC-MS: m/z=380 (M+1).

Example 66 1,1-Dicyclohexyl-3-(4-hydroxymethyl-thiazol-2-yl)urea

Acetic acid-2-(3,3-dicyclohexyl-ureido)-thiazol-4-yl methyl ester (2.4g, 6.3 mmol) was stirred with a solution of potassium carbonate (0.9 g,6.5 mmol) in 2:1 methanol/water at room temperature for 4 hours. Themixture was extracted with ethyl acetate (3×50 mL) and the combinedorganic extracts was dried over sodium sulphate, filtered andconcentrated to obtain1,1-dicyclohexyl-3-(4-hydroxymethyl-thiazol-2-yl)urea (2.0 g).

¹H NMR (CDCl₃): δ 8.95 (1H, s), 6.63 (1H, s), 4.60 (2H, s), 3.46 (2H,m), 1.15-1.90 (20H, m); HPLC-MS: m/z=338 (M+1).

Example 67 Ethyl{2-[dicyclohexylureido]-5-imidazol-1-yl-thiazol-4-yl}-acetic acid

Prepared as described in general procedure (A) using dicyclohexylamineand 5-chloro-(2-amino-4-thiazolyl)acetic acid ethyl ester (prepared bychlorination of 2-aminothiazole-4-acetic acid ethyl ester usingN-chlorosucccinamide in acetic acid at room temperature for 3 h).

HPLC-MS: m/z=460 (M+1).

Example 68 Ethyl {5-Chloro-2-[3-dicyclohexylureido]-thiazol-4-yl}-acetate

Prepared as described in general procedure (A) using dicyclohexylamineand 5-chloro-(2-amino-4-thiazolyl)acetic acid ethyl ester (prepared bychlorination of 2-aminothiazole-4-acetic acid ethyl ester usingN-chlorosucccinamide in acetic acid at room temperature for 3 h).

HPLC-MS: m/z=428 (M+1).

Example 69 1,1-Dicyclohexyl-3-(4,5-dimethyl-thiazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 3,4-dimethyl-2-aminothiazole

HPLC-MS: m/z=336 (M+1).

Example 70 1,1-Dicyclohexyl-3-[1,2,4]thiadiazol-5-yl-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 5-amino-1,2,4-thiadiazole

HPLC-MS: m/z=309 (M+1).

Example 711,1-Dicyclohexyl-3-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-4,5,6,7-tetrahydro-benzothiazole

HPLC-MS: m/z=362 (M+1).

Example 721,1-Dicyclohexyl-3-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-5,6-dihydro-4H-cyclopentathiazole

HPLC-MS: m/z=349 (M+1).

Example 73 3-(5-Chloro-pyridin-2-yl)-1,1-dicyclohexyl-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-5-chloropyridine

HPLC-MS: m/z=336 (M+1).

Example 74 [2-(3,3-Dicyclohexyl-ureido)-5-chloro-thiazol-4-yl]-aceticacid

Prepared from Ethyl{5-Chloro-2-[3-dicyclohexylureido]-thiazol-4-yl}-acetate using generalprocedure (F).

HPLC-MS: m/z=400 (M+1).

Example 75 1,1-Dicyclohexyl-3-(3-methoxy-[1,2,4]thiadiazol-5-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 3-methoxy-5-amino-1,2,4-thiadiazole

HPLC-MS: m/z=339 (M+1).

Example 761,1-Dicyclohexyl-3-(3-methylsulfanyl-[1,2,4]thiadiazol-5-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 3-thiomethoxy-5-amino-1,2,4-thiadiazole

HPLC-MS: m/z=355 (M+1).

Example 77 General Procedure A[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-yl]-acetic acid

Prepared from[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-yl]-acetic acid ethylester as described in general procedure (F).

HPLC-MS: m/z=367 (M+1).

Example 78 1-Cyclohexyl-1-(tetrahydro-pyran-4-yl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and cyclohexyl-(tetrahydro-pyran-4-yl)-amine.

HPLC-MS: m/z=310 (M+1).

Example 791-Cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and cyclohexyl-(tetrahydro-thiopyran-4-yl)-amine.

HPLC-MS: m/z=326 (M+1).

Example 80 4-(1-Cyclohexyl-3-thiazol-2-yl-ureido)-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) usingaminothiazole and 4-cyclohexylamino-cyclohexanecarboxylic acid ethylester

HPLC-MS: m/z=380 (M+1).

Example 813-[4-(1-Cyclohexyl-3-thiazol-2-yl-ureido)-cyclohexyl]-propionic acidethyl ester

Prepared as described in general procedures (A) and (B) usingaminothiazole and 3-(4-cyclohexylamino-cyclohexyl)-propionic acid ethylester

HPLC-MS: m/z=408 (M+1).

Example 82 1-Cyclohexyl-1-(4-oxo-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingaminothiazole and 4-cyclohexylamino-cyclohexanone

HPLC-MS: m/z=322 (M+1).

Example 833-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and cyclohexyl-(tetrahydro-pyran-4-yl)-amine

HPLC-MS: m/z=344 (M+1).

Example 843-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole andcyclohexyl-(tetrahydro-thiopyran-4-yl)-amine

HPLC-MS: m/z=360 (M+1).

Example 854-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and 4-cyclohexylamino-cyclohexanecarboxylicacid ethyl ester

HPLC-MS: m/z=414 (M+1).

Example 863-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-cyclohexyl}-propionicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and 3-(4-cyclohexylamino-cyclohexyl)-propionicacid ethyl ester

HPLC-MS: m/z=442 (M+1).

Example 872-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-cyclohexanecarboxylicacid methyl ester

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and 2-cyclohexylamino-cyclohexanecarboxylicacid ethyl ester

HPLC-MS: m/z=400 (M+1).

Example 883-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(4-oxo-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and 4-cyclohexylamino-cyclohexanone

HPLC-MS: m/z=356 (M+1).

Example 891-Cyclohexyl-3-(5-methyl-thiazol-2-yl)-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and cyclohexyl-(tetrahydro-pyran-4-yl)-amine

HPLC-MS: m/z=324 (M+1).

Example 901-Cyclohexyl-3-(5-methyl-thiazol-2-yl)-1-(tetrahydro-thiopyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole andcyclohexyl-(tetrahydro-thiopyran-4-yl)-amine

HPLC-MS: m/z=340 (M+1).

Example 914-[1-Cyclohexyl-3-(5-methyl-thiazol-2-yl)-ureido]-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and 4-cyclohexylamino-cyclohexanecarboxylicacid ethyl ester

HPLC-MS: m/z=394 (M+1).

Example 923-{4-[1-Cyclohexyl-3-(5-methyl-thiazol-2-yl)-ureido]-cyclohexyl}-propionicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and 3-(4-cyclohexylamino-cyclohexyl)-propionicacid ethyl ester

HPLC-MS: m/z=422 (M+1).

Example 93 General Procedures A and B1-Cyclohexyl-3-(5-methyl-thiazol-2-yl)-1-(4-oxo-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using5-methyl-2-aminothiazole and 4-cyclohexylamino-cyclohexanone

HPLC-MS: m/z=336 (M+1).

Example 94 1-Cyclohexyl-1-piperidin-1-yl-3-thiazol-2-yl-urea

Piperidin-1-yl-amine (0.25 g, 2.5 mmol) and cyclohexanone (0.25 g, 2.5mmol) was dissolved in MeOH (5 mL) and acetic acid ((0.25 mL).Approximately ⅔ of the NaCNBH₃ (0.46 g, 7.49 mmol) was added and thereaction mixture was stirred for 1 h before the last ⅓ was introduced.The reaction mixture was stirred 16 h before the volatiles were removedin vacuo. The residue was separated between EtOAc (50 mL) and semisaturated sodium carbonate (50 mL). The organic phase was dried (MgSO₄),filtered and concentrated in vacuo. The residue was dissolved in1,2-dichloroethane (5 mL) (Solution 1).

Another flask was charged with 2-aminothiazole (0.25 g, 2.5 mmol) in1,2-dichloroethane (10 mL) and CDI (0.40 g, 2.5 mmol)) was added. Themixture was stirred for 1 h before) solution 1 was added. The reactionmixture was stirred for 16 h before the solvent was removed in vacuo.The product was separated between EtOAc (50 mL) and HCl (1N, 50 mL) andthe organic phase was washed with brine (50 mL) and dried (MgSO₄) togive 520 mg of 1-Cyclohexyl-1-piperidin-1-yl-3-thiazol-2-yl-urea.

¹H NMR (CDCl₃): δ 9.85 (s, 1H), 7.35 (d, 1H), 6.83 (d, 1H), 3.30-3.15(m, 1H), 2.90-2.85 (m, 2H), 2.75-2.65 (m, 2H), 2.45-2.35 (m, 2H),1.90-1.60 (m, 12H), 1.35-1.10 (m, 5H) HPLC-MS (Method A): m/z=309 (M+1);R_(t)=3.91 min.

Example 95 1-Cyclohexyl-1-pyrrolidin-1-yl-3-thiazol-2-yl-urea

Procedure as in Example 94 using pyrrolidin-1-yl-amine and cyclohexanone

HPLC-MS (Method A): m/z=295 (M+1); R_(t)=3.60 min.

Example 96 [2-(3,3-Dicyclohexyl-ureido)-5-methyl-thiazol-4-yl]-aceticacid ethyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand 5-methyl-(2-amino-4-thiazolyl)acetic acid ethyl ester

HPLC-MS: m/z=409 (M+1).

Example 97 [2-(3,3-Dicyclohexyl-ureido)-5-ethyl-thiazol-4-yl]-aceticacid ethyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand 5-ethyl-(2-amino-4-thiazolyl)acetic acid ethyl ester

HPLC-MS: m/z=422 (M+1).

Example 98 General Procedure A[2-(3,3-Dicyclohexyl-ureido)-5-methyl-thiazol-4-yl]-acetic acid

Prepared from [2-(3,3-dicyclohexyl-ureido)-5-methyl-thiazol-4-yl]-aceticacid ethyl ester using general procedure (F).

HPLC-MS: m/z=380 (M+1).

Example 994-[3-(5-Chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-cyclohexanecarboxylicacid ethyl ester

Prepared as described in general procedures (A) and (B) using5-chloro-2-aminothiazole and4-(4-methyl-cyclohexylamino)-cyclohexanecarboxylic acid ethyl ester

HPLC-MS: m/z=428 (M+1).

Example 100 General Procedure A1,1-Dicyclohexyl-3-(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-5-cyclopropyl-1,3,4-thiadiazole

HPLC-MS: m/z=349 (M+1).

Example 101 General Procedure A1,1-Dicyclohexyl-3-(5-ethylsulfanyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-5-ethylthio-1,3,4-thiadiazole

HPLC-MS: m/z=369 (M+1).

Example 102 General Procedure A1,1-Dicyclohexyl-3-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-5-trifluoromethyl-1,3,4-thiadiazole

HPLC-MS: m/z=377 (M+1).

Example 103 3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-piperidin-1-yl-urea

1-Cyclohexyl-1-piperidin-1-yl-3-thiazol-2-yl-urea (50 mg, 0.16 mmol),prepared in an identical manner to Example 94 was dissolved in DCM (1mL) and NCS (26 mg, 0.19 mmol)) was added. The reaction mixture wasstirred for 3 days before DCM (20 mL) and water (20 mL) was added. Theorganic phase was dried (MgSO₄) and the solvent was removed in vacuo.MeCN (1 mL) was added whereupon the product precipitated. The productwas filtered off and dried. Yield: 20 mg.

HPLC-MS (Method A): m/z=344 (M+1); R_(t)=5.35 min.

Example 104 3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-morpholin-4-yl-urea

Procedure in an identical manner to Example 94 usingmorpholin-4-yl-amine and cyclohexanone

HPLC-MS (Method A): m/z=346 (M+1); R_(t)=4.32 min

Example 105 [2-(3,3-Dicyclohexyl-ureido)-5-ethyl-thiazol-4-yl]-aceticacid

Prepared from Example 97 using general procedure (F).

HPLC-MS: m/z=394 (M+1).

Example 106[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-acetic acidethyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand ethyl 2-[5-amino-1,3,4-thiadiazol-2-yl)thio]acetate

HPLC-MS: m/z=427 (M+1)

Example 107 6-(3,3-Dicyclohexyl-ureido)-nicotinic acid methyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand methyl-6-amino nicotinate.

HPLC-MS: m/z=360 (M+1).

Example 108[2-(3,3-Dicyclohexyl-ureido)-5-(pyrimidin-2-ylsulfanyl)-thiazol-4-yl]-aceticacid ethyl ester

Prepared as described in general procedure (E) using ethyl{5-Chloro-2-[3-dicyclohexylureido]-thiazol-4-yl}-acetate (Example 68)and 2-mercaptopyrimidine.

HPLC-MS: m/z=504 (M+1).

Example 109[2-(3,3-Dicyclohexyl-ureido)-5-phenylsulfanyl-thiazol-4-yl]-acetic acidethyl ester

Prepared as described in general procedure (E) using ethyl{5-chloro-2-[3-dicyclohexylureido]-thiazol-4-yl}-acetate (Example 68)and thiophenol.

HPLC-MS: m/z=502 (M+1).

Example 110 5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazole-2-carboxylicacid

5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazole-2-carboxylic acid ethylester was prepared from dicyclohexane and 5-amino-1,3,4-thiadiazolecarboxylic acid ethyl ester using general procedures (A) and (B). Esterhydrolysis using lithium hydroxide in methanol gave the title compound.

HPLC-MS: m/z=309 (M+-CO₂).

Example 111[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-acetic acid

Hydrolysis of[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-acetic acidethyl ester using general procedure (F) gave the title compound.

Example 112 1,1-Dicyclohexyl-3-(5-phenyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-5-phenyl-[1,3,4]-thiadiazole

HPLC-MS: m/z=385 (M+1).

Example 113 [5-Bromo-2-(3,3-dicyclohexyl-ureido)-thiazol-4-yl]-aceticacid ethyl ester

[2-(3,3-Dicyclohexyl-ureido)-thiazol-4-yl]-acetic acid ethyl ester wasprepared from dicyclohexylamine and (2-amino-4-thiazolyl)acetic acidethyl ester as described in general procedure (A). To this compound wasadded 1.3 equivalents of N-bromosuccinimide suspended in acetic acid,and the mixture was stirred for 3 h at RT. The reaction mixture wasconcentrated in vacuo, redissolved in dichloromethane, washed with 10%sodium sulphate, water, aqueous sodium bicarbonate, brine and then driedover magnesium sulphate. Flash chromatography afforded the titlecompound.

HPLC-MS: m/z=472 (M+1).

Example 1143-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-furan-(3R)-yl)-urea

Prepared as described in general procedure (A) and (B) using(R)-cyclohexyl-(tetrahydrofuran-3-yl)-amine and 5-chloro-2-aminothiazole

HPLC-MS: m/z=330 (M+1).

Example 115[2-(3,3-Dicyclohexyl-ureido)-5-(pyrimidin-2-ylsulfanyl)-thiazol-4-yl]-aceticacid

Hydrolysis of[2-(3,3-Dicyclohexyl-ureido)-5-(pyrimidin-2-ylsulfanyl)-thiazol-4-yl]-aceticacid ethyl ester using general procedure (F) gave the title compound.

HPLC-MS: m/z=476 (M+1).

Example 116{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-5-ethyl-thiazol-4-yl}-aceticacid

{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-5-ethyl-thiazol-4-yl}-aceticacid ethyl ester was prepared fromcyclopentyl-(4-methyl-cyclohexyl)-amine and5-ethyl-2-aminothiazole-4-acetic acid ethyl ester using generalprocedures (A) and (B). Hydrolysis using general procedure (F) gave thetitle compound.

HPLC-MS: m/z=394 (M+1).

Example 117{2-[3,3-Bis-(4-methyl-cyclohexyl)-ureido]-5-ethyl-thiazol-4-yl}-aceticacid

{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-5-ethyl-thiazol-4-yl}-aceticacid ethyl ester was prepared from bis-(4-methyl-cyclohexyl)-amine and5-ethyl-2-aminothiazole-4-acetic acid ethyl ester using generalprocedures (A) and (B). Hydrolysis using general procedure (F) gave thetitle compound.

HPLC-MS: m/z=422 (M+1).

Example 1183-(5-Chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(4-oxo-cyclohexyl)-urea

Prepared as described in general procedure (A) and (B) using4-(4-Methyl-cyclohexylamino)-cyclohexanone and 5-chloro-2-amino thiazole

HPLC-MS: m/z=370 (M+1).

Example 1191-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-Chloro-thiazol-2-yl)-urea

Prepared as described in general procedure (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone and 5-chloro-2-aminothiazole

HPLC-MS: m/z=365 (M+1).

Example 120 1-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-thiazol-2-yl-urea

Prepared as described in general procedure (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone and 2-amino thiazole

HPLC-MS: m/z=351 (M+1).

Example 121{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester

Prepared as described in general procedure (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester

HPLC-MS: m/z=469 (M+1).

Example 1221-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone and 5-methyl-2-aminothiazole

HPLC-MS: m/z=365 (M+1).

Example 123{2-[3-Cyclohexyl-3-(tetrahydro-furan-(3R)-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester

Prepared as described in general procedure (A) and (B) using(R)-cyclohexyl-(tetrahydro-furan-3-yl)-amine andethyl-2-[5-aminothiazol-2-yl-thio]acetate

HPLC-MS: m/z=414 (M+1).

Example 124{5-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester

Prepared as described in general procedure (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate.

HPLC-MS: m/z=470 (M+1).

Example 1251-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone and2-amino-5-cyclopropyl-1,3,4-thiadiazole

HPLC-MS: m/z=392 (M+1).

Example 1261-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-urea

Prepared as described in general procedure (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone and2-amino-5-trifluoromethyl-1,3,4-thiadiazole

HPLC-MS: m/z=420 (M+1).

Example 127{5-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid

{5-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester was prepared usingcyclopentyl-(4-methyl-cyclohexyl)-amine andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate as described ingeneral procedure (A) and (B). Hydrolysis using general procedure (F)gave the title compound.

HPLC-MS: m/z=399.4 (M+1).

Example 128{5-[3-Cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid

{5-[3-Cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester was prepared usingcyclohexyl-(4-methyl-cyclohexyl)-amine andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate as described ingeneral procedure (A) and (B). Hydrolysis using general procedure (F)gave the title compound.

HPLC-MS: m/z=413.5 (M+1).

Example 129 3-[6-(3,3-Dicyclohexyl-ureido)-pyridin-3-yl]-acrylic acidethyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand 3-(6-aminopyridin-3-yl)-acrylic acid ethyl ester

HPLC-MS: m/z=400.6 (M+1).

Example 130{5-[3-(4-Methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid

{5-[3-(4-Methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester was prepared using(4-methyl-cyclohexyl)-(tetrahydro-pyran-4-yl)-amine andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate as described ingeneral procedure (A) and (B). Hydrolysis using general procedure (F)gave the title compound.

HPLC-MS: m/z=415.5 (M+1).

Example 131 1,1-Dicyclohexyl-3-(1H-imidazol-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-aminoimidazole

HPLC-MS: m/z=292 (M+1).

Example 132{2-[3-Cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-5-ethyl-thiazol-4-yl}-aceticacid

{2-[3-Cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-5-ethyl-thiazol-4-yl}-aceticacid ethyl ester was prepared fromcyclohexyl-(4-methyl-cyclohexyl)-amine and(2-amino-5-ethyl-thiazol-4-yl)-acetic acid ethyl ester using generalprocedures (A) and (B). Hydrolysis using general procedure (F) gave thetitle compound.

HPLC-MS: m/z=408.6 (M+1).

Example 133{5-[3-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid

{5-[3-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester was prepared usingcyclohexyl-(tetrahydro-pyran-4-yl)-amine andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate as described ingeneral procedure (A) and (B). Hydrolysis using general procedure (F)gave the title compound.

HPLC-MS: m/z=401.4 (M+1).

Example 1341,1-Dicyclohexyl-3-[5-(2-dimethylamino-ethylsulfanyl)-thiazol-2-yl]-urea

3-(5-Bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea (1.25 g, 3.24 mmol)(prepared according to general procedure C) in DMF (12 mL) was added2-dimethylamino-ethanethiole hydrochloride (0.92 g, 6.47 mmol) and NaOH(0.97 mL, 9.7 mmol) and the reaction mixture was stirred for 1 h beforethe flask was transferred to a refrigerator and left for 2 days. Thereaction mixture was purified on a preparative HPLC. The fractions werecollected and the volatiles were removed in vacuo. The residue wasdissolved in EtOAc, washed with sodium carbonate and dried (MgSO₄).Yield 152 mg (11%).

¹H NMR (CDCl₃): δ 7.35 (s, 1H), 2.76 (t, 2H), 2.41 (t, 2H), 2.12 (s,6H), 2.0-1.0 (m, 22H) HPLC-MS: m/z=412 (M+1).

Example 1353-5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1,1-dioxo-tetrahydrothiophen-3-yl)-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-(1,1-dioxo-tetrahydrothiophen-3-yl)-amine and5-chloro-2-amino thiazole

HPLC-MS: m/z=379 (M+1).

Example 1362-[5-(3,3-Dicyclohexylureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-N-thiazol-2-ylacetamide

Prepared as described in general procedure (A) using dicyclohexylamineand 5-amino-1,3,4-thiadiazol-2-ylsulfanyl-N-thiazol-2-ylacetamide

HPLC-MS: m/z=481 (M+1).

Example 1371-(1-Butyryl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=413 (M+1).

Example 1381-(1-Propionyl-piperidin-4-yl)-3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=399 (M+1).

Example 139{2-[3-Cyclohexyl-3-(4-oxo-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester

Prepared as described in general procedures (A) and (B) using4-(4-methylcyclohexylamino)-cyclohexanone andethyl-2-[5-aminothiazol-2-yl-thio]acetate

HPLC-MS: m/z=440 (M+1).

Example 1403-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1-cyclopentanecarbonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=439 (M+1).

Example 141{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared from{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester using general procedure (F).

HPLC-MS: m/z=441 (M+1).

Example 1421-(1-Acetyl-piperidin-4-yl)-1-cycloheptyl-3-thiazol-2-yl-urea

Prepared as described in general procedure (G) using4-cycloheptylamino-piperidine-1-carboxylic acid tert-butyl ester and2-aminothiazole

HPLC-MS: m/z=365 (M+1).

Example 1431,1-Dicyclohexyl-3-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-urea

Prepared as described in general procedures (A) using dicyclohexylamineand 2-amino-5-(4-methylpiperazin-1-yl)-thiazole.

HPLC-MS: m/z=406 (M+1).

Example 144{2-[3-Cyclohexyl-3-(4-oxo-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared from{2-[3-Cyclohexyl-3-(4-oxo-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester using general procedure (F).

HPLC-MS: m/z=412 (M+1).

Example 1451-(1-Acetyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-cyclopentyl-urea

Prepared as described in general procedure (G) using4-cyclopentylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=371 (M+1).

Example 1461-Cyclohexyl-1-(1,1-dioxo-tetrahydrothiophen-3-yl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-(1,1-dioxo-tetrahydrothiophen-3-yl)-amine and 2-aminothiazole

HPLC-MS: m/z=344 (M+1).

Example 147{5-[3-Cyclohexyl-3-(4-oxo-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester

Prepared as described in general procedures (A) and (B) using4-cyclohexylamino-cyclohexanone andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate

HPLC-MS: m/z=441 (M+1).

Example 1483-[2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazol-5-ylsulfanyl]-propionicacid

Prepared as described in general procedures (A) and (B) using3-[2-(3,3-dicyclohexyl-ureido)-4-methyl-thiazol-5-ylsulfanyl]-propionicacid ethyl ester and 3-(2-amino-4-methyl-thiazol-5-ylsulfanyl)-propionicacid ethyl ester

HPLC-MS: m/z=426 (M+1).

Example 149{5-[3,3-Bis-(4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid

{5-[3,3-Bis-(4-methyl-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester prepared from bis-(4-methyl-cyclohexyl)-amine andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate as described ingeneral procedures (A) and (B). Hydrolysis using general procedure (F)gave the title compound.

HPLC-MS: m/z=427 (M+1).

Example 1504-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-N-tert-butoxycarbonyl-piperidine

Prepared as described in general procedure (G) using4-cyclopentylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=443 (M+1).

Example 1511-(4-Amino-cyclohexyl)-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedures (A), (B) using(4-cyclohexylamino-cyclohexyl)-carbamic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=357 (M+1).

Example 1524-(1-Cyclohexyl-3-thiazol-2-yl-ureido)-N-tert-butoxycarbonyl-piperidine

Prepared as described in general procedure (G) using4-cyclopentylamino-piperidine-1-carboxylic acid tert-butyl ester and2-aminothiazole

HPLC-MS: m/z=409 (M+1).

Example 1531-(1-Benzoyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedure (G) using4-cyclopentylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=447 (M+1).

Example 154[2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazol-5-ylsulfanyl]-acetic acid

[2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazol-5-ylsulfanyl]-acetic acidethyl ester prepared as described in general procedure (A) usingdicyclohexylamine and 3-methyl-5-aminothiazole-2-mercaptoacetic acidethyl ester. Hydrolysis using general procedure (F) gave the titlecompound.

HPLC-MS: m/z=412 (M+1).

Example 155 4-(3,3-Dicyclohexylureido)furazan-3-carboxylic acid

Prepared as described in general procedure (A) using dicyclohexylamineand 4-amino-3-furazanecarboxylic acid.

HPLC-MS: m/z=337 (M+1).

Example 156[5-(3-Cyclohexyl-3-cyclopentyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-aceticacid

[5-(3-Cyclohexyl-3-cyclopentyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-aceticacid ethyl ester prepared as described in general procedures (A) and (B)using cyclohexyl-cyclopentyl-amine andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z=385 (M+1).

Example 1573-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=448 (M+1).

Example 1581-Cyclohexyl-3-(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-1-(4-oxo-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) using4-cyclohexylamino-cyclohexanone and2-amino-5-cyclopropyl-1,3,4-thiadiazole

HPLC-MS: m/z=363 (M+1).

Example 1594-[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-butyricacid

4-[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-butyricacid ethyl ester was pre-pared as described in general procedure (A)using dicyclohexylamine and4-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-butyric acid ethyl ester.Hydrolysis using general procedure (F) gave the title compound.

HPLC-MS: m/z=427 (M+1).

Example 160{5-[3-Cyclohexyl-3-(4-oxo-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid

Hydrolysis of{5-[3-Cyclohexyl-3-(4-oxo-cyclohexyl)-ureido]-[1,3,4]thiadiazol-2-ylsulfanyl}-aceticacid ethyl ester using general procedure (F) gave the title compound.

HPLC-MS: m/z=413 (M+1).

Example 1613-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1,1-dioxo-tetrahydro-1-thiopyran-4-yl)-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-(1,1-dioxo-thiomorpholine-4-yl)-amine and5-chloro-2-aminothiazole.

HPLC-MS: 392 (M+1).

Example 162 1-Cyclohexyl-1-(4,4-dimethyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-(4,4-dimethyl-cyclohexyl)-amine and 2-amino thiazole

HPLC-MS: m/z=336 (M+1).

Example 163 [2-(3,3-Dicyclohexylureido)benzothiazol-6-yl]acetic acid

Prepared as described in general procedure (A) using dicyclohexylamineand 2-aminobenzthiazole-6-acetic acid.

HPLC-MS: m/z=416 (M+1).

Example 164{2-[3-Cyclohexyl-3-(tetrahydro-furan-(3R)-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Hydrolysis of{2-[3-Cyclohexyl-3-(tetrahydro-furan-(3R)-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester using general procedure (F) gave the title compound.

HPLC-MS: m/z=386 (M+1).

Example 1653-(5-Methyl-thiazol-2-yl)-1-(4-oxo-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedure (A) using4-(tetrahydro-pyran-4-ylamino)-cyclohexanone and2-amino-5-methylthiazole.

HPLC-MS: m/z=339 (M+1).

Example 166[2-(3,3-Dicyclohexyl-ureido)-thiazol-4-ylmethylsulfanyl]-acetic acid

[2-(3,3-Dicyclohexyl-ureido)-thiazol-4-ylmethylsulfanyl]-acetic acidethyl ester prepared as described in general procedure (A) usingdicyclohexylamine and (2-amino-thiazol-4-ylmethylsulfanyl)-acetic acidethyl ester (prepared by reaction of 4-chloromethyl-thiazol-2-ylamine,ethyl-2-mercaptoacetate and potassium carbonate in DMF for 1 h at roomtemperature). Hydrolysis using general procedure (F) gave the titlecompound.

HPLC-MS: m/z=412 (M+1).

Example 1671-(4-tert-butoxycarbonylamino-cyclohexyl)-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedures (A) and (B) using(4-cyclohexylamino-cyclohexyl)-carbamic acid tert-butyl ester and2-amino-5-chlorothiazole

HPLC-MS: m/z=457 (M+1).

Example 1681-(4-tert-butoxycarbonylamino-cyclohexyl)-3-(thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedures (A) and (B) using(4-cyclohexylamino-cyclohexyl)-carbamic acid tert-butyl ester and2-aminothiazole

HPLC-MS: m/z=423 (M+1).

Example 1693-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(4-fluoro-benzoyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=465 (M+1).

Example 1703-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(4-methoxy-benzoyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=477 (M+1).

Example 171[5-(3,3-Dicyclopentyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-aceticacid

[5-(3,3-Dicyclopentyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-aceticacid ethyl ester prepared as described in general procedures (A) and (B)using dicyclopentylamine andethyl-2-[5-amino-1,3,4-thiadiazol-2-yl-thio]acetate. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z=371 (M+1).

Example 1723-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-methoxy-benzoyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z=477 (M+1).

Example 1731,1-Dicyclohexyl-3-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-urea

Step 1: Synthesis of4-Methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine:N-acetamino-5-thiazolesulfonyl chloride (0.9 g; 042 mmol) was dissolvedin DCM (15 ml) TEA (0.71 g; 7.07 mmol) and 1-methyl piperazine (0.42 g;4.24 mmol) were added (Exothermic!) under stirring. The reaction mixturewas stirred for 30 min. Water (15 ml) was added and extracted with DCM(3×25 ml). The organic phase was dried, filtered and evaporation invacuo gave 1.1 g white crystals ofN-[5-(4-Methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-acetamide.

¹H NMR (MeOD): δ 9.5 (br s; 1H); 3.2 (br t; 4H); 2.55 (br t; 4H); 2.50(s; 3H); 2.32 (s; 3H); 2.29 (s; 3H).

Step 2: The above compound was hydrolysed in 6 N HCl/MeOH (1:1) in amicrowave vessel (20 ml). The reaction was heated 3000@80° C.; ×4 beforecomplete conversion. To the reaction mixture was added DCM (10 ml) andstirred for 5 min. The DCM phase was removed; TLC showed no compound inthe organic phase to remove neutral starting material from the firststep! Then the mixture was added base until basic pH. Extraction (3×25ml) DCM, drying with MgSO₄ and evaporation gave 532 mg white crystals of4-Methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine.

HPLC-MS: m/z=277 (M+1).

Prepared in the microwave oven (EmrysOptimizer®).4-Methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine (0.04 g;0.141 mmol), CDI (0.023 g; 0.141 mmol) and DMAP were mixeddichloroethane (1.5 ml) in a microwave vessel (2.5 ml). The reactionmixture was heated 600 sec at 120° C., dicyclohexylamine (0.025 g; 0.141mmol) dissolved in dichloroethane (0.2 ml) was added through the septumand the reaction mixture was heated for additional 600 sec. at 120° C.To the reaction mixture was added water and DCM (25 ml). The water phasewas extracted with DCM (3×25 ml), dried with MgSO₄ filtered andevaporated in vacuo to afford the title compound, (84 mg) as a yellowoil. Purification by prep. HPLC gave 3 mg (Yield: 4%)

HPLC-MS: m/z=484 (M+1).

Example 1743-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic acidmethyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 3-mercaptopropionicacid methyl ester.

¹H NMR (CDCl₃): δ 7.52 (br, 1H), 7.34 (s, 1H), 3.67 (s, 3H), 3.41 (m,2H), 2.91 (t, 2H), 2.61 (t, 3H), 1.05-1.84 (m, 20H) ppm; HPLC-MS: m/z426 (M+1).

Example 1753-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid

Prepared as described in the general procedure (F) from3-[2-(3,3-dicyclohexyl-ureido)thiazol-5-ylsulfanyl]-propionic acidmethyl ester.

¹H NMR (DMSO-d₆): δ 12.62 (br, 1H), 9.86 (br, 1H), 7.94 (s, 1H), 3.51(t, 2H), 3.30 (m, 2H), 2.58 (t, 2H), 1.10-1.88 (m, 20H) ppm; HPLC-MS:m/z 412 (M+1).

Example 1762-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfonyl]-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester

Prepared from2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester (Example 59) as described in general procedure (J).

¹H NMR (CDCl₃): δ 9.23 (br, 1H), 8.15 (br, 1H), 7.69 (s, 1H), 4.35 (q,2H), 4.27 (s, 3H), 3.42 (m, 2H), 1.70-1.86 (m, 16H), 1.36 (t, 3H),1.10-1.48 (m, 4H) ppm; HPLC-MS: m/z 524 (M+1).

Example 1772-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfonyl]-3-methyl-3H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfonyl]-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester (Example 176).

¹H NMR (DMSO-d₆): δ 12.82 (br, 1H), 9.42 (br, 1H), 8.22 (s, 1H), 7.68(s, 1H), 4.19 (s, 3H), 3.42 (m, 2H), 1.02-1.96 (m, 20H) ppm; HPLC-MS:m/z 496 (M+1).

Example 1782-[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-sulfonyl]-1H-imidazole-4-carboxylicacid ethyl ester

Prepared from2-[2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfanyl]-1H-imidazole-4-carboxylicacid ethyl ester (Example 57) as described in general procedure (J).

¹H NMR (CDCl₃): δ 9.34 (br, 1H), 8.10 (br, 1H), 7.79 (s, 1H), 4.36 (q,2H), 3.43 (m, 2H), 1.15-1.86 (m, 23H) ppm; HPLC-MS: m/z 510 (M+1).

Example 1792-[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-sulfonyl]-1H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-[2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonyl]-1H-imidazole-4-carboxylicacid ethyl ester (Example 178).

¹H NMR (DMSO-d₆): δ 12.34 (br, 1H), 9.28 (br, 1H), 8.09 (s, 1H), 7.94(s, 1H), 3.33 (m, 2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 482 (M+1).

Example 1801,1-Dicyclohexyl-3-[5-(pyrimidine-2-sulfonyl)-thiazol-2-yl]-urea

Prepared from1,1-dicyclohexyl-3-[5-(pyrimidine-2-sulfanyl)-thiazol-2-yl]-urea asdescribed in general procedure (J).

¹H NMR (CDCl₃): δ 9.18 (br, 1H), 8.92 (d, 2H), 8.10 (s, 1H), 7.51 (t,1H), 3.45 (m, 2H), 1.15-1.85 (m, 20H) ppm; HPLC-MS: m/z 450 (M+1).

Example 181 [2-(3,3-Dicyclohexyl-ureido)-thiazole-5-sulfonyl]-aceticacid methyl ester

Prepared from [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfanyl]-aceticacid methyl ester (Example 54) as described in general procedure (J)

¹H NMR (CDCl₃): δ 7.96 (br, 1H), 7.26 (s, 1H), 4.18 (s, 2H), 3.77 (s,1H), 3.42 (m, 2H), 1.19-1.86 (m, 20H) ppm; HPLC-MS: m/z 444 (M+1).

Example 182 [2-(3,3-Dicyclohexyl-ureido)-thiazole-5-sulfonyl]-aceticacid

Prepared as described in the general procedure (F) from[2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonyl]-acetic acid methylester (Example 181).

¹H NMR (DMSO-d₆): δ 12.12 (br, 1H), 8.22 (br, 1H), 7.95 (s, 1H), 4.46(s, 2H), 3.42 (m, 2H), 1.08-1.90 (m, 20H) ppm; HPLC-MS: m/z 430 (M+1).

Example 1831,1-Dicyclohexyl-3-[5-(4-methyl-4H-[1,2,4]triazole-3-sulfonyl)-thiazol-2-yl]-urea

Prepared from1,1-dicyclohexyl-3-[5-(4-methyl-4H-[1,2,4]triazole-3-sulfanyl)-thiazol-2-yl]-ureaas described in general procedure (J).

¹H NMR (CDCl₃): δ 8.88 (br, 1H), 8.17 (s, 1H), 8.11 (br, 1H), 4.01 (s,3H), 3.42 (m, 2H), 1.11-1.85 (m, 20H) ppm; HPLC-MS: m/z 453 (M+1).

Example 1841,1-Dicyclohexyl-3-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-urea

Prepared from1,1-dicyclohexyl-3-[5-(pyridine-2-sulfanyl)-thiazol-2-yl]-urea (Example56) as described in general procedure (J).

¹H NMR (CDCl₃): δ 8.86 (br, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 8.07 (s,1H), 7.91 (m, 1H), 7.46 (m, 1H) 3.39 (m, 2H), 1.16-1.84 (m, 20H) ppm;HPLC-MS: m/z 449 (M+1).

Example 1852-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-nicotinic acidmethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 2-mercaptonicotinicacid methylester.

HPLC-MS: m/z 475 (M+1).

Example 1862-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-nicotinic acid

Prepared as described in the general procedure (F) from2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-nicotinic acidmethyl ester (Example 185).

¹H NMR (DMSO-d₆): δ 12.33 (br, 1H), 9.24 (br, 1H), 8.51 (m, 1H), 8.22(m, 1H), 7.44 (s, 1H), 7.27 (m, 1H), 3.48 (m, 2H), 1.05-1.97 (m, 20H)ppm; HPLC-MS: m/z 461 (M+1).

Example 1873-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfonyl]-propionic acidmethyl ester

Prepared from3-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic acidmethyl ester as described in general procedure (J).

HPLC-MS: m/z 458 (M+1).

Example 1883-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfonyl]-propionic acid

Prepared as described in the general procedure (F) from3-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfonyl]-propionic acidmethyl ester (Example 187).

HPLC-MS: m/z 444 (M+1).

Example 1893-(5-Bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedure (C) usingcyclohexyl-(tetrahydro-pyran-4-yl)-amine and 5-bromo-2-thiazolyl amine.

¹H NMR (CDCl₃): δ 9.22 (s, 1H), 7.02 (s, 1H), 4.05 (dd, 2H), 3.87 (br,1H), 3.48 (t, 2H), 3.40 (br, 1H), 1.26-2.28 (m, 14H) ppm; HPLC-MS: m/z389 (M+1).

Example 1903-(5-Bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea

Prepared as described in general procedure (C) usingcyclohexyl-(tetrahydro-thiopyran-4-yl)-amine and 5-bromo-2-thiazolylamine.

¹H NMR (CDCl₃): δ 8.11 (s, 1H), 7.24 (s, 1H), 3.57 (m, 1H), 3.38 (m,1H), 2.75 (m, 4H), 1.14-2.17 (m, 14H) ppm; HPLC-MS: m/z 405 (M+1).

Example 1913-(5-Bromo-thiazol-2-yl)-1-cyclohexyl-1-(1,1-dioxo-tetrahydro-thiopyran-4-yl)-urea

Prepared from3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea(Example 190) as described in the general procedure (J).

HPLC-MS: m/z 437 (M+1).

Example 192{2-[3-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea andmethyl thioglycolate

¹H NMR (CDCl₃): δ 8.26 (br, 1H), 7.41 (s, 1H), 4.05 (dd, 2H), 3.89 (br,1H), 3.72 (s, 3H), 3.44 (m 2H), 3.41 (s, 2H), 3.35 (m, 1H), 1.15-2.19(m, 14H) ppm; HPLC-MS: m/z 414 (M+1).

Example 193{2-[3-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (F) from{2-[3-cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester (Example 192).

¹H NMR (DMSO-d₆): δ 12.44 (br, 1H), 8.5 (br, 1H), 7.38 (s, 1H), 3.83 (m,2H), 3.67 (m, 1H), 3.45 (s, 2H), 3.32-3.38 (m, 3H), 1.09-2.20 (m, 14H)ppm; HPLC-MS: m/z 400 (M+1).

Example 194{2-[3-Cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea(Example 190) and methyl thioglycolate.

HPLC-MS: m/z 430 (M+1).

Example 195{2-[3-Cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (F) from{2-[3-cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 12.34 (br, 1H), 11.2 (br, 1H), 7.37 (s, 1H), 3.45(s, 2H), 3.31 (m, 2H), 2.73 (m, 2H), 2.55 (m, 2H), 1.15-2.12 (m, 14H)ppm; HPLC-MS: m/z 416 (M+1).

Example 1962-{2-[3-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea(Example 189) and ethyl-2-mercapto-1H-imidazole-4-carboxylate.

HPLC-MS: m/z 480 (M+1).

Example 1972-{2-[3-Cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-{2-[3-cyclohexyl-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₆): δ 13.02 (br, 1H), 11.23 (br, 1H), 7.86 (s, 1H), 7.59(s, 1H), 3.84 (m, 2H), 3.37 (m, 4H), 1.21-2.40 (m, 14H) ppm; HPLC-MS:m/z 452 (M+1).

Example 1983-{2-[3-Cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea(Example 190) and 3-mercaptopropionic acid methyl ester.

¹H NMR (CDCl₃): δ 9.40 (br, 1H), 7.35 (s, 1H), 3.69 (s, 3H), 3.61 (br,1H), 3.41 (br, 1H), 2.94 (t, 2H), 2.80 (t, 2H), 2.69 (dd, 2H), 2.61 (t,2H), 1.18-2.20 (m, 14H) ppm; HPLC-MS: m/z 444 (M+1).

Example 1993-{2-[3-Cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described in the general procedure (F) from3-{2-[3-cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester (Example 198).

¹H NMR (DMSO-d₆): δ 12.40 (br, 1H), 8.42 (br, 1H), 7.35 (s, 1H), 3.82(m, 2H), 2.82 (t, 2H), 2.76 (dd, 2H), 2.57 (dd, 2H), 2.49 (t, 2H),1.20-2.23 (m, 14H) ppm; HPLC-MS: m/z 430 (M+1).

Example 2002-{2-[3-Cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea(Example 190) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acidethyl ester.

¹H NMR (CDCl₃): δ 8.20 (br, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.53 (s,1H), 4.29 (q, 2H), 3.96 (s, 3H), 3.58 (br, 1H), 3.39 (br, 1H), 2.65-2.78(m, 4H), 1.18-2.24 (m, 17H) ppm; HPLC-MS: m/z 510 (M+1).

Example 2012-{2-[3-Cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-{2-[3-cyclohexyl-3-(tetrahydro-thiopyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester (Example 200).

¹H NMR (DMSO-d₆): δ 12.24 (br, 1H), 7.61 (br, 1H), 7.57 (s, 1H), 7.53(s, 1H), 3.87 (s, 3H), 3.36 (m, 2H), 2.72 (t, 2H), 2.55 (d, 2H),1.04-1.89 (m, 14H) ppm; HPLC-MS: m/z 482 (M+1).

Example 2023-(5-Bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (C) usingcyclopentyl-(4-methyl-cyclohexyl)-amine and 5-bromo-2-thiazolyl amine.

¹H NMR (CDCl₃): δ 8.50 (br, 1H), 7.26 (1H, s), 3.83 (m, 1H), 3.48 (m,1H), 1.07-1.90 (m, 17H, m), 0.82-1.05 (dd, 3H) ppm; HPLC-MS: m/z 387(M+1).

Example 2033-(5-Bromo-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea

Prepared as described in general procedure (C) using(4-methyl-cyclohexyl)-(tetrahydro-pyran-4-yl)-amine and5-bromo-2-thiazolyl amine.

¹H NMR (CDCl₃): δ 8.44 (br, 1H), 7.27 (1H, s), 4.02 (d, 2H), 3.82 (m,2H), 3.41 (t, 2H), 3.32 (m, 1H), 1.05-2.09 (m, 13H), 0.89-1.03 (dd, 3H)ppm; HPLC-MS: m/z 403 (M+1).

Example 2043-(5-Bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-trifluoromethyl-cyclohexyl)-urea

Prepared as described in general procedure (C) usingcyclohexyl-(4-trifluoromethyl-cyclohexyl)-amine and 5-bromo-2-thiazolylamine.

¹H NMR (CDCl₃): δ 8.15 (br, 1H), 7.26 (1H, s), 3.70 (m, 1H), 3.32 (m,1H), 1.15-2.07 (m, 19H), 0.89-1.03 (dd, 3H) ppm; HPLC-MS: m/z 455 (M+1).

Example 205{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea(Example 202) and methyl thioglycolate.

¹H NMR (CDCl₃): δ 8.44 (br, 1H), 7.39 (s, 1H), 3.83 (m, 1H), 3.70 (s,3H), 3.49 (m, 1H), 3.41 (s, 2H), 1.12-1.87 (m, 17H), 0.87-1.01 (dd, 3H)ppm; HPLC-MS: m/z 412 (M+1).

Example 206{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (F) from{2-[3-cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester (Example 205).

¹H NMR (DMSO-d₆): δ 11.94 (br, 1H), 8.42 (br 1H), 7.37 (s, 1H), 3.82 (m,1H), 3.56 (m, 1H), 3.45 (s, 2H), 1.14-1.98 (m, 17H), 0.83-0.97 (dd, 3H)ppm; HPLC-MS: m/z 398 (M+1).

Example 2073-{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea(Example 202) and 3-mercaptopropionic acid methyl ester.

HPLC-MS: m/z 426 (M+1).

Example 2083-{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described in the general procedure (F) from3-{2-[3-cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester (Example 207).

¹H NMR (DMSO-d₆): δ 11.44 (br, 1H), 8.54 (br 1H), 7.34 (s, 1H), 3.82 (m,1H), 3.56 (m, 1H), 3.33 (s, 1H), 2.08 (t, 2H), 2.43 (t, 2H), 1.06-1.98(m, 17H), 0.83-0.97 (dd, 3H) ppm; HPLC-MS: m/z 412 (M+1).

Example 2092-{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea(Example 202) and ethyl-2-mercapto-1H-imidazole-4-carboxylate.

¹H NMR (CDCl₃): δ 9.22 (br, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 4.30 (q,2H), 3.82 (m, 1H), 3.44 (m, 1H), 1.34-1.82 (m, 20H), 0.78-0.98 (dd, 3H)ppm; HPLC-MS: m/z 478 (M+1).

Example 2102-{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-{2-[3-cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₆): δ 12.92 (br, 1H), 11.94 (br, 1H), 7.82 (br, 1H), 7.56(s, 1H), 3.82 (m, 1H), 3.56 (m, 1H), 1.08-1.97 (m, 17H), 0.83-0.96 (dd,3H) ppm; HPLC-MS: m/z 450 (M+1).

Example 2112-{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea(Example 202) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acidethyl ester.

¹H NMR (CDCl₃): δ 9.24 (br, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 4.28 (q,2H), 3.98 (s, 3H), 3.83 (m, 1H), 3.50 (m, 1H), 1.01-1.84 (m, 20H),0.82-0.98 (dd, 3H) ppm; HPLC-MS: m/z 492 (M+1).

Example 2122-{2-[3-Cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from2-{2-[3-cyclopentyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester.

¹H NMR (DMSO-d₆): δ 12.96 (br, 1H), 11.45 (br, 1H), 7.61 (br, 1H), 7.56(s, 1H), 3.86 (s, 3H), 3.81 (m, 1H), 3.56 (m, 1H), 1.03-1.99 (m, 17H),0.83-0.96 (dd, 3H) ppm; HPLC-MS: m/z 464 (M+1).

Example 213{2-[3-(4-Methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea(Example 203) and methyl thioglycolate.

¹H NMR (CDCl₃): δ 8.28 (br, 1H), 7.41 (s, 1H), 4.05 (m, 2H), 3.85 (m,2H), 3.72 (s, 3H), 3.42 (m, 2H), 3.33 (m, 1H), 1.05-2.26 (m, 13H),0.90-1.06 (dd, 3H) ppm; HPLC-MS: m/z 428 (M+1).

Example 214{2-[3-(4-Methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (F) from{2-[3-(4-methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester (Example 213).

¹H NMR (DMSO-d₆): δ 12.2 (br, 1H), 7.6 (br, 1H), 7.36 (s, 1H), 3.82 (m,2H), 3.70 (br, 1H), 3.45 (s, 2H), 3.35 (m, 3H), 1.02-2.26 (m, 13H),0.84-0.99 (dd, 3H) ppm; HPLC-MS: m/z 414 (M+1).

Example 2153-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-3H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromo-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea(Example 203) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acidethyl ester.

¹H NMR (CDCl₃): δ 9.36 (br, 1H), 8.06 (br, 1H), 7.68 (s, 1H), 7.55 (s,1H), 4.30 (q, 2H), 4.04 (m, 2H), 3.98 (s, 3H), 3.80 (m, 1H), 3.43 (m,2H), 3.31 (m, 1H), 1.34-1.82 (m, 13H), 0.78-0.98 (dd, 3H) ppm; HPLC-MS:m/z 508 (M+1).

Example 2163-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-3H-imidazole-4-carboxylicacid

Prepared as described in general procedure (F) from3-methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(tetrahydro-pyran-4-yl)-ureido]-thiazol-5-ylsulfanyl}-3H-imidazole-4-carboxylicacid ethyl ester (Example 215).

¹H NMR (DMSO-d₆): δ 12.26 (br, 1H), 7.8 (br, 1H), 7.61 (s, 1H), 7.54 (s,1H), 3.87 (s, 3H), 3.81 (m, 3H), 3.48 (m, 1H), 3.36 (m, 2H), 1.03-2.20(m, 13H), 0.83-0.96 (dd, 3H) ppm; HPLC-MS: m/z 480 (M+1).

Example 217{2-[3-Cyclohexyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-trifluoromethyl-cyclohexyl)-urea(Example 204) and methyl thioglycolate.

¹H NMR (CDCl₃): δ 7.62 (br, 1H), 7.34 (s, 1H), 3.66 (s, 3H), 3.37 (s,2H), 3.28 (m, 2H), 1.05-2.26 (m, 19H) ppm; HPLC-MS: m/z 480 (M+1).

Example 218{2-[3-Cyclohexyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (F) from{2-[3-cyclohexyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester (Example 217).

¹H NMR (DMSO-d₆): δ 12.16 (br, 1H), 7.37 (s, 1H), 3.44 (s, 3H), 3.32 (m,2H), 1.05-2.21 (m, 19H) ppm; HPLC-MS: m/z 466 (M+1).

Example 2193-{2-[3-Cyclohexyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester

Prepared as described in general procedure (D) using3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-trifluoromethyl-cyclohexyl)-urea(Example 204) and 3-mercaptopropionic acid methyl ester.

HPLC-MS: m/z 494 (M+1).

Example 220 [2-(3,3-Dicyclohexyl-ureido)-thiazol-5-yl]-acetic acidmethyl ester

Prepared as described in general procedure (C) using dicyclohexylamineand 2-amino-thiazol-5-yl)-acetic acid methyl ester.

¹H NMR (CDCl₃): δ 7.25 (s, 1H), 7.13 (br, 1H), 3.71 (s, 5H), 3.42 (m,2H), 1.05-1.99 (m, 20H) ppm; HPLC-MS: m/z 380 (M+1).

Example 221 [2-(3,3-Dicyclohexyl-ureido)-thiazol-5-yl]-acetic acid

Prepared as described in the general procedure (F) from[2-(3,3-dicyclohexyl-ureido)-thiazol-5-yl]-acetic acid methyl ester(Example 220).

¹H NMR (DMSO-d₆): δ 12.16 (br, 1H), 7.29 (br, 1H), 7.10 (s, 1H), 3.65(s, 2H), 3.44 (m, 2H), 1.05-1.97 (m, 20H) ppm; HPLC-MS: m/z 366 (M+1).

Example 222 1,1-Dicyclohexyl-3-(4-formyl-thiazol-2-yl)-urea

To a solution of 1,1-dicyclohexyl-3-(4-hydroxymethyl-thiazol-2-yl)urea(850 mg, 2.5 mmol) in 4:1 DCM/DMSO (8 mL) was added pyridine-sulfurtrioxide (1.59 g, 10.0 mmol) and triethyl-amine (1.55 mL, 11.25 mmol) at0° C. The mixture was stirred for 6 h and quenched with water (50 mL)and the layers were separated. The aqueous layer was extracted with DCM(2×50 mL). The combined organic layers was washed with water, saturatedammonium chloride solution, brine, dried over sodium sulfate andconcentrated in vacuo to obtain1,1-dicyclohexyl-3-(4-formyl-thiazol-2-yl)urea (800 mg, 2.38 mmol).

¹H NMR (CDCl₃): δ 9.78 (s, 1H), 8.2 (br, 1H), 7.74 (s, 1H), 3.45 (m,2H), 1.20-1.90 (m, 20H) ppm; HPLC-MS: m/z 336 (M+1).

Example 223 [2-(3,3-Dicyclohexylureido)-thiazol-4-yl]acetic acid ethylester

Prepared in 63% yield as described in general procedure (C) fromdicyclohexylamine and ethyl-2-amino-4-thiazoleacetate.

¹H NMR (CDCl₃): δ 8.00 (br, 1H), 6.65 (s, 1H), 3.63 (s, 3H), 3.46 (m,2H), 1.15-1.90 (m, 23H) ppm; HPLC-MS: m/z 394 (M+1).

Example 224 3-(4-Cyano-thiazol-2-yl)-1,1-dicyclohexylurea

Prepared as described in general procedure (C) using dicyclohexyl amineand 4-cyano-2-thiazolyl amine.

¹H NMR (4:1 CDCl₃-CD₃OD): δ 8.16 (br, 1H), 7.55 (s, 1H), 3.44 (m, 2H),1.15-1.90 (m, 20H) ppm; HPLC-MS: m/z 333 (M+1).

Example 2251,1-Dicyclohexyl-3-[4-(methanesulfonylhydroxyimino-methyl)-thiazol-2-yl]urea

To a solution of1,1-dicyclohexyl-3-[4-(hydroxyimino-methyl)-thiazol-2-yl]-urea (0.15mmol) in DCM (4 mL) was added methanesulfonyl chloride (0.15 mmol) andDIEA (0.15 mL). The mixture was stirred at rt for 2 h and quenched withwater (10 mL). The reaction mixture was extracted with ethyl acetate(3×10 mL). The combined organic extracts was washed with water (2×30mL), dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography (silica,EtOAc/hexanes 1:4 to EtOAc/hexanes 1:1) to give the desired product in30% yield.

¹H NMR (4:1 CDCl₃-CD₃OD): δ 8.60 (s, 1H), 7.80 (s, 1H), 6.48 (d, 1H),3.60 (br, 2H), 3.40 (s, 3H), 1.15-1.90 (m, 20H) ppm; HPLC-MS: m/z 429(M+1).

Example 226 1,1-Dicyclohexyl-3-[4-(1-methyl-1H-tetrazol-5-ylsulfanylmethyl)thiazol-2-yl]urea

Prepared in 20% yield as described in general procedure (L) from1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and1-methyl-5-mercaptotetrazole.

¹H NMR (d6-acetone): δ 6.84 (s, 1H), 4.47 (s, 2H), 3.93 (s, 3H), 3.60(br, 2H), 2.80 (br, 1H), 1.15-1.90 (m, 20H) ppm; HPLC-MS: m/z 436 (M+1).

Example 2272-[2-(3,3-Dicyclohexylureido)-thiazol-4-ylmethylsulfanyl)-1H-imidazole-4-carboxylicacid ethyl ester

Prepared in 20% yield as described in general procedure (L) from1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester.

HPLC-MS: m/z 492 (M+1).

Example 228N-[2-(3,3-Dicyclohexylureido)-thiazol-4-ylmethyl]-methansulfonamide

To a solution of1,1-dicyclohexyl-3-[4-(hydroxyimino-methyl)-thiazol-2-yl]-urea (150 mg,0.45 mmol) was added borane-THF complex (5.0 mL 1.0M) and the contentwas stirred for 2 h at rt. The mixture was quenched with NaHCO₃ solutionand extracted with ethyl acetate (2×30 mL). The organic extracts waswashed (2×30 mL), dried over sodium sulfate, filtered and concentratedin vacuo to get the corresponding amine. To this amine in DCM (5.0 mL)was added methansulfonyl anhydride (0.1 mL) and DIEA (0.2 mL) at 0° C.The mixture was evaporated and the crude product was purified by flashchromatography (silica, CH₂CH₂-EtOAc 1:4) to furnishN-[2-(3,3-dicyclohexylureido)-thiazol-4-ylmethyl]-methansulfonamide (20mg) in 10% yield.

¹H NMR (CD₃OD): δ 6.90 (d, 1H), 4.20 (s, 2H), 3.46 (br, 1H), 3.30 (m,2H), 2.80 (s, 2H), 1.15-1.90 (m, 20H) ppm; HPLC-MS: m/z 415 (M+1).

Example 2291,1-Dicyclohexyl-3-[4-(pyridin-2-ylsulfanylmethyl)-thiazol-2-yl]urea

Prepared as described in general procedure (L) from1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and2-mercaptopyridine.

¹H NMR (d6-DMSO): δ 8.40 (d, 1H), 7.64 (m, 1H), 7.30 (d, 1H), 7.11 (m,1H), 6.85 (s, 1H), 4.34 (s, 2H), 3.46 (m, 2H), 1.15-1.90 (m, 20H) ppm;HPLC-MS: m/z 431 (M+1).

Example 2301,1-Dicyclohexyl-3-[4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-thiazol-2-yl]urea

Prepared as described in general procedure (L) from1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and2-mercapto-1-methyl-1H-imidazole.

¹H NMR (4:1 CDCl₃-CD₃OD): δ 7.21 (d, 1H), 7.04 (d, 1H), 6.94 (d, 1H),6.85 (s, 1H), 3.44 (m, 2H), 3.40 (s, 2H), 3.32 (s, 3H), 1.10-1.90 (m,20H) ppm; HPLC-MS: m/z 434 (M+1).

Example 231{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}acetic acidmethyl ester

Prepared in 75% yield as described in general procedure (K) using2-(3,3-dicyclohexylureido)-thiazole-5-carboxylic acid and glycine methylester hydrochloride.

¹H NMR (4:1 CDCl₃-CD₃OD): δ 8.06 (s, 1H), 7.65 (s, 1H), 4.24 (d, 2H),3.80 (s, 3H), 3.46 (br, 2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 423(M+1).

Example 2321-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}cyclopropanecarboxylicacid ethyl ester

Prepared in 82% yield as described in general procedure (K) using2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid and1-aminocyclopropane-1-carboxylic acid ethyl ester.

¹H NMR (d6-DMSO): δ 7.92 (s, 1H), 4.04 (q, 2H), 6.48 (d, 1H), 3.48 (m,2H), 1.00-2.00 (m, 27H) ppm; HPLC-MS: m/z 463 (M+1).

Example 233(S)-1-[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-piperidine-3-carboxylicacid

Prepared in 90% yield as described in general procedure (F) byhydrolysis of(S)-1-[2-(3,3-dicyclohexylureido)-thiazole-5-carbonyl]-piperidine-3-carboxylicacid ethyl ester (Example 234).

¹H NMR (d6-DMSO): δ 7.64 (s, 1H), 4.20 (d, 1H), 3.95 (d, 1H), 3.40 (m,2H), 3.10 (m, 1H), 1.15-1.90 (m, 26H) ppm; HPLC-MS: m/z 463 (M+1).

Example 234(S)-1-[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-piperidine-3-carboxylicacid ethyl ester

Prepared in 98% yield (120 mg) as described in general procedure (K)using 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid and(S)-nipecotic acid ethyl ester.

¹H NMR (4:1 CDCl₃-CD₃OD): δ 7.64 (s, 1H), 4.10 (d, 1H), 4.06 (q, 2H),3.95 (d, 1H), 3.45 (m, 2H), 3.20 (t, 1H), 1.35-1.90 (m, 20H), 1.15 (t,3H) ppm; HPLC-MS: m/z 491 (M+1).

Example 235{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-acetic acid

Prepared in 90% yield as described in general procedure (F) byhydrolysis of{[2-(3,3-dicyclohexylureido)-thiazole-5-carbonyl]-amino}acetic acidmethyl ester (Example 231).

HPLC-MS: m/z 409 (M+1).

Example 2363-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acidmethyl ester

Prepared in 21% yield as described in general procedure (K) using2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid and methyl-3-aminobenzoate.

¹H NMR (d6-DMSO: δ 8.60 (t, 1H), 7.94 (m, 2H), 7.70 (d, 1H), 7.50 (t,1H), 7.40 (t, 1H), 3.60 (s, 3H), 3.46 (m, 2H), 1.15-1.90 (m, 20H) ppm;HPLC-MS: m/z 485 (M+1).

Example 237 3-(5-Bromothiazol-2-yl)-1,1-bis-4-methylcyclohexyl)urea

Prepared in 52% yield as described in general procedure (C) usingbis(4-methylcyclohexyl)amine and 2-amino-5-bromothiazole.

¹H NMR (4:1 CDCl₃-CD₃OD): δ 7.95 (br, 1H), 7.24 (s, 1H), 3.46 (m, 2H),1.15-1.90 (m, 18H), 0-95-1.10 (two d, 6H) ppm; HPLC-MS: m/z 415 (M+1).

Example 238{2-[3,3-Bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}acetic acidmethyl ester

Prepared in 41% yield as described in general procedure (D) using3-(5-bromothiazol-2-yl)-1,1-bis-4-methylcyclohexyl)urea (Example 237)and methylthioglycolate.

¹H NMR (CDCl₃): δ 8.16 (br, 1H), 7.35 (s, 1H), 3.70 (s, 3H), 3.5 (m,2H), 1.15-1.90 (m, 18H), 0.91-1.05 (two d, 6H) ppm; HPLC-MS: m/z 440(M+1).

Example 239{2-[3,3-Bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}acetic acid

Prepared in 85% yield as described in general procedure (F) from{2-[3,3-bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}acetic acidmethyl ester (Example 238).

¹H NMR (CDCl₃): δ 8.20 (br, 1H), 7.4 (s, 1H), 3.72 (s, 3H), 3.4 (s, 2H),3.30 (m, 2H), 1.15-1.90 (m, 18H), 0.90-1.05 (two d, 6H) ppm; HPLC-MS:m/z 426 (M+1).

Example 240 [2-(3,3-Dicyclohexylureido)thiazol-5-ylmethylsulfanyl]aceticacid methyl ester

Prepared as described in general procedure (K) from1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and methylthioglycolate.

HPLC-MS: m/z 426 (M+1).

Example 2413-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-propionicacid ethyl ester

Prepared in 21% yield as described in general procedure (K) using2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid and beta-alanineethyl ester hydrochloride.

HPLC-MS: m/z 451 (M+1).

Example 2423-(5-Bromothiazol-2-yl)-1-cyclohexyl-1-(4-methylcyclohexyl)-urea

Prepared as described in general procedure (C) using4-methylcyclohexyl-cyclohexylamine and 2-amino-5-bromothiazole.

¹H NMR (CDCl₃): δ 8.0 (s, 1H), 7.25 (s, 1H), 6.48 (d, 1H), 3.48 (m, 2H),1.15-1.90 (m, 19H), 0.88-1.05 (two d, 3H) ppm; HPLC-MS: m/z 401 (M+1).

Example 2433-{2-[[3,3-Bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}propionicacid methyl ester

Prepared in 20% yield as described in general procedure (D) using3-(5-bromothiazol-2-yl)-1,1-bis-4-methylcyclohexyl)urea (Example 237)and 3-mercapaptoproionic acid methyl ester.

¹H NMR (CDCl₃): δ 8.16 (br, 1H), 7.35 (s, 1H), 3.70 (s, 3H), 3.5 (m,2H), 2.92 (t, 2H), 2.61 (t, 2H), 1.15-1.90 (m, 18H), 0.91-1.05 (2d, 6H)ppm; HPLC-MS: m/z 454 (M+1).

Example 2443-{2-[3,3-Bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}propionicacid

Prepared in 85% yield as described in general procedure (F) byhydrolysis of3-{2-[[3,3-bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}propionicacid methyl ester.

¹H NMR (CDCl₃): δ 7.27 (s, 1H), 3.75 (d, 2H), 3.0 (m, 2H), 2.26 (t, 2H),1.15-1.90 (m, 18H), 0.91-1.05 (two d, 6H) ppm; HPLC-MS: m/z 440 (M+1).

Example 2454-{2-[3,3-Bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}benzoicacid ethyl ester

Prepared as described in general procedure (E) using3-(5-bromothiazol-2-yl)-1,1-bis-4-methylcyclohexyl)urea (Example 237)and 4-mercapto-benzoic acid methyl ester.

¹H NMR (CDCl₃): δ 8.10 (br, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.53 (t,1H), 7.21 (s, 1H), 7.19 (s, 1H), 3.58 (s, 3H), 3.46 (m, 2H), 1.15-2.00(m, 18H), 0.93-1.05 (two d, 6H) ppm; HPLC-MS: m/z 502 (M+1).

Example 2462-{-2-[3-Cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester

Prepared as described in general procedure (E) from3-(5-bromothiazol-2-yl)-1-cyclohexyl-1-(4-methylcyclohexyl)-urea(Example 242) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acidethyl ester.

¹H NMR (4:1 CDCl₃-CD₃OD): δ 7.69 (s, 1H), 7.57 (s, 1H), 4.31 (q, 2H),4.0 (s, 3H), 3.38 (m, 2H), 1.15-1.90 (m, 19H), 1.35 (t, 3H), 0.90-1.10(two d, 3H) ppm; HPLC-MS: m/z 506 (M+1).

Example 247{2-[3-Cyclohexyl-3-(4-methylcyclohexyl)ureideo]thiazol-5-ylsulfanyl}aceticacid methyl ester

Prepared as described in general procedure (E) using3-(5-bromothiazol-2-yl)-1-cyclohexyl-1-(4-methylcyclohexyl)-urea(Example 242) and methyl thioglycolate.

¹H NMR (CDCl₃): δ 7.43 (s, 1H), 7.48 (s, 1H), 3.77 (s, 3H), 3.79 (d,1H), 3.50 (d, 1H), 3.46 (m, 2H), 1.15-1.90 (m, 19H) ppm; 0.90-1.05 (twod, 3H) ppm; HPLC-MS: m/z 426 (M+1).

Example 2483-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-propionicacid

Prepared in 90% yield as described in general procedure (F) from3-{[2-(3,3-dicyclohexyl-ureido)-thiazole-5-carbonyl]-amino}-propionicacid methyl ester (Example 241).

¹H NMR (d6-DMSO): δ 7.80 (s, 1H), 7.67 (s, 1H), 3.56 (t, 2H), 3.46 (m,2H), 2.76 (t, 2H), 1.15-1.90 (m, 20H) ppm; HPLC-MS: m/z 423 (M+1).

Example 2494-{2-[3,3-Bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}benzoicacid

Prepared in 80% yield as described in general procedure (F) from4-{2-[3,3-bis(4-methylcyclohexyl)ureideo]thiazole-5-ylsulfanyl}benzoicacid ethyl ester (Example 245).

¹H NMR (d₆-acetone): δ 7.84 (d, 2H), 7.35 (s, 1H), 7.18 (d, 2H), 3.40(m, 2H), 1.15-1.90 (m, 18H), 0.95-1.05 (two d, 6H) ppm; HPLC-MS: m/z 488(M+1).

Example 250{2-[3-Cyclohexyl-3-(4-methylcyclohexyl)ureideo]thiazol-5-ylsulfanyl}aceticacid

Prepared in 88% yield as described in general procedure (F) from{2-[3-cyclohexyl-3-(4-methylcyclohexyl)ureideo]thiazol-5-ylsulfanyl}aceticacid methyl ester (Example 247).

¹H NMR (4:1 CDCl₃-CD₃OD): δ 7.39 (s, 1H), 7.06 (s, 1H), 3.38 (obscuredby MeOH peak), 1.15-1.90 (m, 19H), 0.95-1.05 (two d, 3H) ppm; HPLC-MS:m/z 412 (M+1).

Example 2512-{-2-[3-Cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid

Prepared in 80% yield as described in general procedure (F) from2-{-2-[3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-3H-imidazole-4-carboxylicacid ethyl ester (Example 246).

¹H NMR (4:1 CDCl₃-CD₃OD): δ 7.80 (s, 1H), 7.56 (s, 1H), 4.00 (s, 3H),3.36 (m, 2H), 1.15-1.90 (m, 19H), 0.95-1.05 (two d, 3H) ppm; HPLC-MS:m/z 478 (M+1)

Example 252 1,1-Dicyclohexyl-3-5-formyl-thiazol-2-yl)-urea

2-Amino-5-formylthiazole (215 mg, 1.67 mmol), carbonyldiimidazole (275mg, 1.70 mmol) and a catalytic amount of DMAP were heated together in 5mL THF at 40° C. for 2 h. To this solution was added dicyclohexylamine(0.34 mL, 1.70 mmol) and the reaction mixture was stirred for anadditional 6 h at room temperature. The reaction mixture wasconcentrated and the crude product was purified by flash chromatography(silica, CH₂Cl₂-EtOAc, 4:1) to obtain1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea.

HPLC-MS: m/z 336 (M+1).

Example 253 2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acidmethoxy-methylamide

Prepared as described in general procedure (K) using2-(3,3-dicyclohexyl-ureido)-thiazole-5-carboxylic acid and methoxymethylamine.

HPLC-MS: m/z 395 (M+1).

Example 2541,1-Dicyclohexyl-3-[5-(pyrrolidine-1-carbonyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (K) using2-(3,3-dicyclohexyl-ureido)-thiazole-5-carboxylic acid and pyrrolidine.

HPLC-MS: m/z 405 (M+1).

Example 255(4-{[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carbonyl]-amino}-phenyl)-aceticacid ethyl ester

Prepared as described in general procedure (K) using2-(3,3-dicyclohexyl-ureido)-thiazole-5-carboxylic acid and4-aminophenylacetic acid ethylester.

HPLC-MS: m/z 513 (M+1).

Example 256(4-{[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carbonyl]-amino}-phenyl)-aceticacid

Prepared in 80% yield as described in general procedure (F) from(4-{[2-(3,3-dicyclohexyl-ureido)-thiazole-5-carbonyl]-amino}-phenyl)-aceticacid ethyl ester (Example 255).

HPLC-MS: m/z 483 (M+1).

Example 257 3-[2-(3,3-Dicyclohexylureido)-thiazol-5-yl]-acrylic acidethyl ester

A solution of 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (Example252) (90 mg, 0.27 mmol) and (carbethoxymethylene)triphenylphosphorane(102 mg, 0.30 mmol) in THF (5 mL) was stirred at 40° C. for 12 h. Thereaction mixture was concentrated and the residue was purified by flashchromatography (silica, CH₂Cl₂-EtOAc, 4:1) to obtain3-[2-(3,3-dicyclohexylureido)-thiazol-5-yl]-acrylic acid ethyl ester (75mg) in 69% yield.

HPLC-MS: m/z 406 (M+1).

Example 258 3-[2-(3,3-Dicyclohexylureido)-thiazol-5-yl]-propionic acidethyl ester

To a solution of 3-[2-(3,3-dicyclohexylureido)-thiazol-5-yl]-acrylicacid ethyl ester (Example 257) (75 mg, 0.18 mmol) in methanol was addedPd/C (150 mg). The content was degassed and was placed under hydrogenatmosphere for 12 h. The mixture was filtered through celite, and thefiltrate was concentrated. The residue was further purified by flashchromatography (silica, CH₂Cl₂-EtOAc 4:1 to give3-[2-(3,3-dicyclohexylureido)-thiazol-5-yl]-propionic acid ethyl ester(35 mg) in 47% yield.

HPLC-MS: m/z 408 (M+1).

Example 259 3-[2-(3,3-Dicyclohexylureido)l-thiazol-5-yl]-propionic acid

Prepared as described in general procedure (F) from3-[2-(3,3-dicyclohexylureido)-thiazol-5-yl]-propionic acid ethyl ester(Example 258).

HPLC-MS: m/z 380 (M+1).

Example 260 1,1-Dicyclohexyl-3-(5-methylisoxazol-3-yl)urea

Prepared as described in general procedure (A) using dicyclohexylamineand 3-amino-5-methylisoxazole

HPLC-MS: m/z=306 (M+1).

Example 261{2-[3-(1-Acetyl-piperidin-4-yl)-3-cycloheptyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (G) using1-(4-cycloheptylamino-piperidin-1-yl)-ethanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester.

HPLC-MS: m/z=455 (M+1)

Example 262{2-[3-(1-Acetyl-piperidin-4-yl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (G) using1-[4-(4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester.

HPLC-MS: m/z=455 (M+1)

Example 263{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclopentyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (G) using1-(4-cyclopentylamino-piperidin-1-yl)-ethanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester.

HPLC-MS: m/z=427 (M+1)

Example 2641-(1-Acetyl-piperidin-4-yl)-1-(4-methyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedure (G) using1-[4-(4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and2-aminothiazole.

HPLC-MS: m/z=365 (M+1)

Example 2651-(1-Acetyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (G) using1-[4-(4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and2-amino-5-chlorothiazole.

HPLC-MS: m/z=399 (M+1)

Example 2661,1-Dicyclohexyl-3-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-urea

Prepared as described in general procedure (A) using dicyclohexylamineand 2-amino-5-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridine

HPLC-MS: m/z=378 (M+1)

Example 2671,1-Dicyclohexyl-3-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-urea

Step 1. Preparation of precursor6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-ylamine. To 4-ketotetrahydropyran(4.1 g) in ether (15 mL) at ice bath temperature was added bromine (6.5g), dropwise over 30 min. After 20 min was added ethyl acetate andsodium carbonate. The aqueous phases was separated and extracted withethyl acetate. The combined organic phases were dried over magnesiumsulfate and concentrated in vacuo, redissolved in ethanol, and thiourea(2.8 g) was added. The mixture was warmed to reflux for 1 h, cooled andthe desired product was isolated by filtration and washed with ether,dried in vacuo, and used directly in Step 2.

Step 2. Urea coupling as described in general procedure (C) gave thetitle compound.

HPLC-MS: m/z=365 (M+1)

Example 2683-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1-methanesulfonyl-piperidin-3-yl)-urea

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and2-amino-5-chlorothiazole as described in general procedure (G).

HPLC-MS: m/z=422 (M+1)

Example 269(2-{3-Cyclohexyl-3-[1-(2,2-dimethyl-propionyl)-pyrrolidin-3-yl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared from 3-amino-1-Boc-pyrrolidine, cyclohexanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester as described in generalprocedure (G).

HPLC-MS: m/z=469 (M+1)

Example 270{2-[3-Cyclohexyl-3-(1-cyclopentanecarbonyl-pyrrolidin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared from 3-amino-1-Boc-pyrrolidine, cyclohexanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester as described in generalprocedure (G).

HPLC-MS: m/z=481 (M+1)

Example 271(2-{3-Cyclohexyl-3-[1-(thiophene-2-carbonyl)-pyrrolidin-3-yl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared from 3-amino-1-Boc-pyrrolidine, cyclohexanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester as described in generalprocedure (G).

HPLC-MS: m/z=495 (M+1)

Example 272{2-[3-(1-Benzoyl-pyrrolidin-3-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared from 3-amino-1-Boc-pyrrolidine, cyclohexanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester as described in generalprocedure (G).

HPLC-MS: m/z=489 (M+1).

Example 273(2-{3-Cyclohexyl-3-[1-(pyridine-3-carbonyl)-pyrrolidin-3-yl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared from 3-amino-1-Boc-pyrrolidine, cyclohexanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester as described in generalprocedure (G).

HPLC-MS: m/z=490 (M+1)

Example 2742-[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-2-methyl-propionicacid

Prepared as described in general procedure (A) using dicyclohexylamineand tert-butyl2-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-2-methylpropanoate.

HPLC-MS: m/z=427 (M+1)

Example 275N-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-cyclohexyl}-acetamide

Prepared from N-Boc-aminocyclohexanone, cyclohexylamine and5-chloro-2-aminothiazole using general procedure (G).

HPLC-MS: m/z=399 (M+1)

Example 276N-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-cyclohexyl}-methanesulfonamide

Prepared from N-Boc-aminocyclohexanone, cyclohexylamine and5-chloro-2-aminothiazole using general procedure (G).

HPLC-MS: m/z=435 (M+1)

Example 2771-(1-Acetyl-piperidin-3-yl)-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and5-chloro-2-aminothiazole using general procedure (G) as described ingeneral procedure (G).

HPLC-MS: m/z=384 (M+)

Example 2781-(1-Acetyl-piperidin-3-yl)-1-cyclohexyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and5-methyl-2-aminothiazole using general procedure (G) as described ingeneral procedure (G).

HPLC-MS: m/z=366 (M+1)

Example 279 1-(1-Acetyl-piperidin-3-yl)-1-cyclohexyl-3-thiazol-2-yl-urea

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and2-aminothiazole using general procedure (G) as described in generalprocedure

HPLC-MS: m/z=351 (M+1)

Example 280{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-5-methyl-thiazol-4-yl}-aceticacid ethyl ester

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and5-methyl-(2-amino-4-thiazolyl)acetic acid ethyl ester using generalprocedure (G).

HPLC-MS: m/z=451 (M+1)

Example 281{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-5-chloro-thiazol-4-yl}-aceticacid ethyl ester

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and5-chloro-(2-amino-4-thiazolyl)acetic acid ethyl ester using generalprocedure (G).

HPLC-MS: m/z=471 (M+1)

Example 282N-[4-(1-Cyclohexyl-3-thiazol-2-yl-ureido)-cyclohexyl]-acetamide

Prepared from N-Boc-aminocyclohexanone, cyclohexylamine and2-aminothiazole using general procedure (G).

HPLC-MS: m/z=365 (M+1)

Example 283N-[4-(1-Cyclohexyl-3-thiazol-2-yl-ureido)-cyclohexyl]-methanesulfonamide

Prepared from N-Boc-aminocyclohexanone, cyclohexylamine and2-aminothiazole using general procedure (G).

HPLC-MS: m/z=401 (M+1)

Example 2841-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-[4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-urea

Prepared as described for Example 173 using4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine and1-(4-cyclohexylamino-piperidin-1-yl)-ethanone.

HPLC-MS: m/z=527 (M+1)

Example 285 1-Cyclobutyl-1-cyclohexyl-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-cyclobutyl-amine and 2-aminothiazole

HPLC-MS: m/z=281 (M+1).

Example 286 1-Cycloheptyl-1-cyclohexyl-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-cycloheptyl-amine and 2-aminothiazole

HPLC-MS: m/z=322 (M+1).

Example 287{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester was prepared as described in general procedures (A) and(B) using cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazol-2-mercaptoacetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z=412 (M+1).

Example 2881-Cyclopentyl-3-(5-methyl-thiazol-2-yl)-1-(1-propionyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-methylthiazole.

HPLC-MS: m/z=365 (M+1)

Example 2891-(1-Butyryl-piperidin-4-yl)-1-cyclopentyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-methylthiazole.

HPLC-MS: m/z=401 (M+Na)

Example 2901-(1-Cyclopentanecarbonyl-piperidin-4-yl)-1-cyclopentyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-methylthiazole.

HPLC-MS: m/z=427 (M+Na)

Example 291{2-[3-Cyclopentyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclopentyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester was prepared as described in general procedures (A) and(B) using cyclopentyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazol-2-mercaptoacetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z=398 (M+1).

Example 292{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-5-methyl-thiazol-4-yl}-aceticacid

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and5-methyl-(2-amino-4-thiazolyl)acetic acid ethyl ester using generalprocedure (G).

HPLC-MS: m/z=424 (M+1)

Example 293{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-5-imidazol-1-yl-thiazol-4-yl}-aceticacid

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and5-methyl-(2-amino-4-thiazolyl)acetic acid ethyl ester using generalprocedure (G).

HPLC-MS: m/z=475 (M+1)

Example 294{2-[3-(1-Acetyl-piperidin-4-yl)-3-cyclohexyl-ureido]-5-chloro-thiazol-4-yl}-aceticacid

Prepared from 3-amino-1-Boc-piperidine, cyclohexanone and5-chloro-(2-amino-4-thiazolyl)acetic acid ethyl ester using generalprocedure (G).

HPLC-MS: m/z=443 (M+1).

Example 2951,1-Dicyclohexyl-3-[5-(2-dimethylamino-ethylsulfanyl)-4-methyl-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea anddimethylaminoethylchloride.

HPLC-MS: m/z=425 (M+1)

Example 2961,1-Dicyclohexyl-3-[5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-urea

Prepared as described for Example 173 using5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine anddicyclohexylamine.

HPLC-MS: m/z=527 (M+1)

Example 2973-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(1-propionyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=385 (M+1)

Example 2981-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-[5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-urea

Prepared as described for Example 173 using5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine and1-(4-cyclohexylamino-piperidin-1-yl)-ethanone.

HPLC-MS: m/z=513 (M+1)

Example 2991-(1-Acetyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (G) using1-[4-(trans-4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and5-chloro-2-aminothiazole.

HPLC-MS: m/z=399 (M+1)

Example 300{2-[3-(1-Acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (G)1-[4-(trans-4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

HPLC-MS: m/z=455 (M+1)

Example 3012-(3,3-Dicyclohexyl-ureido)-5-methylsulfanyl-thiazole-4-carboxylic acid

2-(3,3-Dicyclohexyl-ureido)-5-methylsulfanyl-thiazole-4-carboxylic acidethyl ester was pre-pared as described in general procedure (H) using2-(3,3-dicyclohexyl-ureido)-5-thiocyanato-thiazole-4-carboxylic acidethyl ester and methyl iodide. Hydrolysis using general procedure (F)gave the title compound.

HPLC-MS: m/z=399 (M+1)

Example 3021,1-Dicyclohexyl-3-[4-methyl-5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea andN-(2-chloroethyl)piperidine.

HPLC-MS: m/z=580 (M+1)

Example 3031,1-Dicyclohexyl-3-[4-methyl-5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea andN-(2-chloroethyl)pyrrolidine.

HPLC-MS: m/z=566 (M+1)

Example 3041-(1-Butyryl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-cyclopentyl-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=421 (M+Na)

Example 3053-(5-Chloro-thiazol-2-yl)-1-(1-cyclopentanecarbonyl-piperidin-4-yl)-1-cyclopentyl-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=425 (M+1)

Example 3063-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(1-ethanesulfonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=421 (M+1)

Example 3073-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-[1-(propane-1-sulfonyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclopentnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=435 (M+1)

Example 3081-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(4-methyl-5-methylsulfanyl-thiazol-2-yl)-urea

Prepared as described in general procedure (H) and (I)

HPLC-MS: m/z=412 (M+1)

Example 3091,1-Dicyclohexyl-3-[4-methyl-5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea andN-(2-chloroethyl)morpholine.

HPLC-MS: m/z=582 (M+1)

Example 3103-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1-pentanoyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=427 (M+1)

Example 3113-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3-methyl-butyryl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=427 (M+1)

Example 3123-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-methoxy-acetyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=415 (M+1)

Example 3133-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3,3-dimethyl-butyryl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexanone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=463 (M+Na)

Example 3143-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3-piperidin-1-yl-propionyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=483 (M+1)

Example 3153-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-pyridin-3-yl-acetyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=462 (M+1)

Example 3163-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3-cyclopentyl-propionyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=490 (M+Na)

Example 3173-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(4-dimethylamino-butyryl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=456 (M+1)

Example 3183-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3,3,3-trifluoro-propionyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=453 (M+1)

Example 3194-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-piperidin-1-yl}-4-oxo-butane-1-sulfonicacid amide

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=492 (M+1)

Example 3203-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3-methoxy-propionyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=429 (M+1)

Example 3211-Cyclohexyl-3-(5-methyl-thiazol-2-yl)-1-(1-propionyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-methylthiazole

HPLC-MS: m/z=379 (M+1)

Example 3221-(1-Butyryl-piperidin-4-yl)-1-cyclohexyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-methylthiazole

HPLC-MS: m/z=393 (M+1)

Example 3231-(1-Acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using1-[4-(trans-4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and2-amino-5-methylthiazole

HPLC-MS: m/z=379 (M+1)

Example 3241-(trans-4-Methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-1-(1-propionyl-piperidin-4-yl)urea

Prepared as described in general procedure (G) using4-(4-Methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-methylthiazole

HPLC-MS: m/z=393 (M+1)

Example 3251-(1-Butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using4-(4-Methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-methylthiazole

HPLC-MS: m/z=407 (M+1)

Example 326{2-[3-Cyclopentyl-3-(cis-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (G).

HPLC-MS: m/z=398 (M+1)

Example 3271-[1-(3-Methoxy-propionyl)-piperidin-4-yl]-1-(trans-4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using4-(4-Methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-methylthiazole

HPLC-MS: m/z=423 (M+1)

Example 3281-(4-Methyl-cyclohexyl)-3-(trans-5-methyl-thiazol-2-yl)-1-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-(4-Methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-methylthiazole

HPLC-MS: m/z=433 (M+1)

Example 329 3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-indan-2-yl-urea

Prepared from indane, cyclohexanone and 2-amino-5-methylthiazole asdescribed in general procedures (A) and (B)

HPLC-MS: m/z=376 (M+1)

Example 330 2-(3,3-Dicyclohexylureido)-4-methylthiazole-5-sulfonic acidpiperidin-4-ylamide

4-[2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazole-5-sulfonylamino]-piperidine-1-carboxylicacid ethyl ester was prepared as described in Example 173 using ethyl4-amino-1-piperidine carboxylate, dicyclohexylamine and2-acetylamino-thiazole-5-sulfonyl chloride. Reaction with 33% HBr inacetic acid followed by chromatography afforded the title compound.

HPLC-MS: m/z=484 (M+1)

Example 3313-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=437 (M+1)

Example 332(S)-(2-{3-Cyclohexyl-3-[1-(thiophene-2-carbonyl)-pyrrolidin-3-yl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared from (3S)-3-amino-1-Boc-pyrrolidine, cyclohexanone and5-aminothiazol-2-mercaptoacetic acid ethyl ester as described in generalprocedure (G).

HPLC-MS: m/z=481 (M+1).

Example 3331-(1-Benzenesulfonyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=483 (M+1)

Example 3343-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1-methanesulfonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=421 (M+1).

Example 3353-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=487 (M+1).

Example 3363-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1-ethanesulfonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=435 (M+1).

Example 337trans-3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-phenyl-ethenesulfonyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=509 (M+1).

Example 3383-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cyclohexnone and 2-amino-5-chlorothiazole

HPLC-MS: m/z=513 (M+1).

Example 3391-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-urea

Prepared as described in general procedure (H) and (I) using4-[1-cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester and methyl iodide.

HPLC-MS: m/z=397 (M+1).

Example 3401-Cyclohexyl-3-(5-methyl-thiazol-2-yl)-1-[1-(2,2,2-trifluoro-acetyl)-pyrrolidin-3-yl]-urea

Prepared 3-amino-1-Boc-pyrrolidine and cyclohexanone as described ingeneral procedure (G).

HPLC-MS: m/z=405 (M+1).

Example 3411-(1-Acetyl-pyrrolidin-3-yl)-1-cyclohexyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared 3-amino-1-Boc-pyrrolidine, cyclohexanone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=351 (M+1).

Example 342[2-(3-Cyclohexyl-3-indan-2-yl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

Prepared from indane, cyclohexanone and 5-aminothiazol-2-mercaptoaceticacid ethyl ester as described in general procedures (A) and (B)

HPLC-MS: m/z=432 (M+1).

Example 3433-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-(1-propionyl-piperidin-4-yl)urea

Prepared as described in general procedure (G) using4-(4-methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-chlorothiazole

HPLC-MS: m/z=413 (M+1).

Example 3441-(1-Butyryl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (G) using4-(4-Methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-chlorothiazole

HPLC-MS: m/z=427 (M+1).

Example 3451-Cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-1-[1-(thiophene-2-carbonyl)-piperidin-4-yl]-urea

4-[1-Cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester was prepared as described in general procedure (H)and (I) using4-[1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester, dithioerythritol and methyl iodide. Removal ofthe Boc group and N-acylation using thiophene-2 carboxylic acid asdescribed in general procedure (G), steps 3 and 4 gave the titlecompound.

HPLC-MS: m/z=466 (M+1).

Example 3461-(1-Butyryl-piperidin-4-yl)-1-cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-urea

Prepared as described in general procedure (H) and (I) using1-(1-butyryl-piperidin-4-yl)-1-(4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and methyliodide.

HPLC-MS: m/z=426 (M+1).

Example 3471-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)-morpholine

HPLC-MS: m/z=497 (M+1).

Example 3481-Cyclohexyl-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-1-[1-(thiophene-2-carbonyl)-piperidin-4-yl]-urea

4-{1-Cyclohexyl-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-ureido}-piperidine-1-carboxylicacid tert-butyl ester was prepared as described in general procedure (H)and (I) using4-[1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester, dithioerythritol andN-(2-chloroethyl)-morpholine. Removal of the Boc group and N-acylationusing thiophene-2 carboxylic acid as described in general procedure (G),steps 3 and 4 gave the title compound.

HPLC-MS: m/z=565 (M+1).

Example 3493-(5-Chloro-thiazol-2-yl)-1-[1-(3-methyl-butyryl)-piperidin-4-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (G) using4-(4-Methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-chlorothiazole

HPLC-MS: m/z=441 (M+1).

Example 3503-(5-Chloro-thiazol-2-yl)-1-[1-(2-methoxy-acetyl)-piperidin-4-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (G) using4-(4-Methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester and 2-amino-5-chlorothiazole

HPLC-MS: m/z=429 (M+1).

Example 3511,1-Dicyclohexyl-3-[5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland 1-(2-chloroethyl)-piperidine

HPLC-MS: m/z=566 (M+1).

Example 3521,1-Dicyclohexyl-3-[5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland 1-(2-chloroethyl)-pyrrolidine

HPLC-MS: m/z=556 (M+1).

Example 3531,1-Dicyclohexyl-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland N-(2-chloroethyl)-morpholine

HPLC-MS: m/z=568 (M+1).

Example 3543-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(6-oxo-piperidin-3-yl)-urea

Prepared from (4S)-aminovalerolactam, cyclohexanone and2-amino-5-chlorothiazole as described in general procedures (A) and (B).

HPLC-MS: m/z=357 (M+1).

Example 3551-(1-Butyryl-piperidin-4-yl)-1-cycloheptyl-3-(5-methyl-thiazol-2-yl)-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=407 (M+1).

Example 3561-Cycloheptyl-3-(5-methyl-thiazol-2-yl)-1-(1-propionyl-piperidin-4-yl)-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=393 (M+1).

Example 3571-Cycloheptyl-1-(1-cyclopentanecarbonyl-piperidin-4-yl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=433 (M+1).

Example 3581-Cycloheptyl-1-(1-methanesulfonyl-piperidin-4-yl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=415 (M+1).

Example 3591-Cycloheptyl-3-(5-methyl-thiazol-2-yl)-1-[1-(propane-1-sulfonyl)-piperidin-4-yl]-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=443 (M+1).

Example 3603-(5-Chloro-thiazol-2-yl)-1-cyclopentyl-1-(1-methanesulfonyl-piperidin-4-yl)-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=407 (M+1).

Example 3611-Cycloheptyl-1-(1-ethanesulfonyl-piperidin-4-yl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=429 (M+1).

Example 362[2-(3-Cyclohexyl-3-cyclopentyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

Prepared as described in general procedures (A) and (B) and (F) usingcyclopentyl-cyclohexyl-amine 5-aminothiazol-2-mercaptoacetic acid ethylester.

HPLC-MS: m/z=384 (M+1).

Example 3631-Cyclopentyl-3-(5-methyl-thiazol-2-yl)-1-(1-phenylmethanesulfonyl-piperidin-4-yl)-urea

Prepared from cycloheptylamine, N-Boc-piperidone and2-amino-5-methylthiazole as described in general procedure (G).

HPLC-MS: m/z=415 (M+1).

Example 364[2-(3-Cycloheptyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

[2-(3-Cycloheptyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidethyl ester prepared as described in general procedure (A) usingcyclohexyl-cycloheptylamine and 5-aminothiazole-2-mercaptoacetic acidethyl ester. Hydrolysis using general procedure (F) gave the titlecompound.

HPLC-MS: m/z 412 (M+1).

Example 365{2-[3-Cycloheptyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-Cycloheptyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester prepared as described in general procedures (A) and (B)using cycloheptyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 426 (M+1).

Example 3661-(1-Cyclopentanecarbonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-chlorothiazole

HPLC-MS: m/z 434 (M+1).

Example 3671-(1-Acetyl-piperidin-4-yl)-3-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-diethylamino-ethanethiol

HPLC-MS: m/z 496 (M+1).

Example 368{2-[3-Cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedures (A) and (B) and (F) usingtrans-4-propoxy-cyclohexyl]-cyclohexyl-amine and5-aminothiazole-2-mercaptoacetic acid ethyl ester.

HPLC-MS: m/z 456 (M+1).

Example 3693-{2-[3-Cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described in general procedures (A) and (B) and (F) usingtrans-4-propoxy-cyclohexyl]-cyclohexyl-amine and5-aminothiazole-2-mercaptopropionic acid ethyl ester.

HPLC-MS: m/z 470 (M+1).

Example 3703-{2-[3-Cyclohexyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared in 80% (383 mg) yield as described in the general procedure Ffrom3-{2-[3-cyclohexyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester (494 mg, 1.0 mmol).

¹H NMR (Acetone-d₆): δ 7.39 (br 1H), 7.31 (s, 1H), 3.62 (m, 1H), 3.51(m, 1H), 2.93 (t, 2H), 2.63 (t, 2H), 2.1 (m, 1H), 1.06-2.01 (m, 18H)ppm; HPLC-MS: m/z 480 (M+1).

Example 371Trans-3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-methyl-cyclohexyl)-urea

Prepared in 60% (240 mg) yield as described in general procedure C usingtrans-4-methylcyclohexyl-cyclohexylamine (195 mg, 1.0 mmol) and2-amino-5-bromothiazole (179 mg, 1.0 mmol).

¹H NMR (CDCl₃): δ 8.4 (br, 1H), 7.25 (s, 1H), 3.48 (m, 2H), 1.12-1.99(m, 19H), 0.90 (d, 3H) ppm; HPLC-MS: m/z 401 (M+1).

Example 372Trans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea

Prepared in 40% (140 mg) yield as described for1,1-dicyclohexyl-3-5-formyl-thiazol-2-yl)-urea usingcyclohexyl-(trans-4-methyl-cyclohexyl)-amine (195 mg, 1.0 mmol) and2-amino-5-formylthiazole (128 mg, 1.0 mmol).

¹H NMR (CDCl₃): δ 9.9 (s, 1H), 8.92 (br, 1H), 7.99 (s, 1H), 3.42 (m,2H), 1.04-1.92 (m, 19H), 0.90 (d, 3H) ppm; HPLC-MS: m/z 350 (M+1).

Example 3731-cyclohexyl-3-(5-hydroxymethyl-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea

To a solution of1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea(175 mg, 0.5 mmol) in MeOH (5 mL) was added sodium borohydride (38 mg, 1mmol). The mixture was stirred at rt for 10 min and the solution waspoured into water (25 mL). The aqueous layer was extracted with ethylacetate (2×20 mL). The organic layer was washed with water (2×20 mL),brine (1×20 mL), dried (anhydrous Na₂SO₄) and concentrated to gettrans-1-cyclohexyl-3-(5-hydroxymethyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureain (90%, 158 mg) yield.

¹H NMR (CDCl₃): δ 9.20 (m, 1H), 7.22 (s, 1H), 4.74 (s, 2H), 3.63 (br,1H), 3.43 (m, 2H), 1.04-1.85 (m, 19H), 0.89 (d, 3H) ppm; HPLC-MS: m/z352 (M+1).

Example 374(S)-2-tert-Butoxycarbonylamino-3-{2-[trans-3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester

Prepared in 60% (333 mg) yield as described in general procedure (D)usingtrans-3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-methyl-cyclohexyl)-urea(400 mg, 1.0 mmol) and N-(tert-butoxycarbonyl)-L-cysteine methyl ester(470 mg, 2.0 mmol).

¹H NMR (CDCl₃): δ 7.39 (br, 1H), 7.32 (s, 1H), 6.84 (d, 1H), 3.66 (s,3H), 3.40 (m, 3H), 3.16 (m, 2H), 1.64-1.82 (m, 16H), 1.44 (s, 9H),1.1-1.43 (m, 3H), 0.90 (d, 3H) ppm; HPLC-MS: m/z 555 (M+1).

Example 375(S)-2-tert-Butoxycarbonylamino-3-{2-[trans-3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared in 70% (95 mg) yield as described in general procedure (F) from(S)-2-tert-butoxycarbonylamino-3-{2-[trans-3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester (139 mg, 0.25 mmol).

HPLC-MS: m/z 541 (M+1).

Example 376(S)-2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-1-methoxycarbonyl-ethyl-ammoniumchloride

Prepared in 75% (86 mg) yield as described in general procedure (M) from(S)-2-tert-butoxycarbonylamino-3-{2-[(3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester (139 mg, 0.25 mmol).

HPLC-MS: m/z 456 (M+1).

Example 377(S)-1-Carboxy-2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-ethyl-ammoniumchloride

Prepared in 70% (77 mg) yield as described in general procedure (M) from(S)-2-tert-butoxycarbonylamino-3-{2-[(trans)-3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid (135 mg, 0.25 mmol).

HPLC-MS: m/z 442 (M+1).

Example 3784-{1-Cyclohexyl-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidine-1-carboxylicacid tert-butyl ester

Prepared in 50% (299 mg) yield as described in general procedure (B)from4-[1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester (436 mg, 1.0 mmol) and 1-ethanesulfonyl-piperazinehydrochloride (215 mg, 1.0 mmol).4-[1-Cyclohexyl-3-(5-formyl-thiazol-2-yl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester (50%, 218 mg) was prepared as described in theprocedure for 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester (282 mg,1.0 mmol) and 2-amino-5-formylthiazole (128 mg, 1.0 mmol).

HPLC-MS: m/z 599 (M+1).

Example 3794-{1-Cyclohexyl-3-[5-(4-dimethylsulfamoyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidine-1-carboxylicacid tert-butyl ester

Prepared in 55% (338 mg) yield as described in general procedure (B)from4-[1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester (436 mg, 1.0 mmol) and piperazine-1-sulfonic aciddimethylamide hydrochloride (230 mg, 1.0 mmol).

HPLC-MS: m/z 614 (M+1).

Example 3804-{2-[3-Cyclohexyl-3-(1-cyclopentanecarbonyl-piperidin-4-yl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide

Prepared in 75% (229 mg) yield as described in general procedure (N)from4-{1-cyclohexyl-3-[5-(4-dimethylsulfamoyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium;chloride (275 mg, 0.5 mmol) and cyclopentanecarbonyl chloride (80 mg,0.6 mmol).

¹H NMR (CDCl₃): δ 7.52 (br, 1H), 7.09 (s, 1H), 4.76 (d, 2H), 4.04 (d,2H), 3.76 (m, 2H), 3.64 (s, 2H), 3.26 (m, 4H), 2.87-3.10 (m, 1H), 2.81(s, 6H), 2.52 (m, 4H), 1.15-2.14 (m, 22H) ppm;

HPLC-MS: m/z 610 (M+1).

Example 3814-{2-[3-(1-Butyryl-piperidin-4-yl)-3-cyclohexyl-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide

Prepared in 70% (204 mg) yield as described in general procedure (N)from4-{1-cyclohexyl-3-[5-(4-dimethylsulfamoyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium;chloride (275 mg) and butyryl chloride (64 mg, 0.6 mmol).

¹H NMR (CDCl₃): δ 7.30 (br, 1H), 7.11 (s, 1H), 4.75 (d, 2H), 3.94 (d,2H), 3.78 (m, 2H), 3.65 (s, 2H), 3.27 (m, 4H), 3.06 (t, 1H), 2.83 (s,6H), 2.52 (m, 4H), 2.32 (t, 2H), 1.05-2.21 (m, 16H), 0.95 (t, 3H) ppm;HPLC-MS: m/z 584 (M+1).

Example 3821-Cyclohexyl-1-(1-cyclopentanecarbonyl-piperidin-4-yl)-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-urea

Prepared in 65% (193 mg) yield as described in general procedure (N)from4-{1-cyclohexyl-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium;chloride (268 mg, 0.5 mmol) and cyclopentanecarbonyl chloride (80 mg,0.6 mmol).

¹H NMR (CDCl₃): δ 7.52 (br, 1H), 7.08 (s, 1H), 4.78 (d, 2H), 4.06 (d,2H), 3.8 (m, 2H), 3.65 (s, 2H), 3.29 (m, 4H), 2.87-3.03 (m, 3H), 2.54(m, 4H), 1.54-2.12 ((m, 20H), 136 (t, 3H), 1.05-1.32 (m, 2H) ppm;HPLC-MS: m/z 595 (M+1).

Example 383Trans-1-cyclohexyl-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-urea

Prepared in 60% (307 mg) yield as described in general procedure (B)fromtrans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea(349 mg, 1.0 mmol) and 1-ethanesulfonyl-piperazine hydrochloride (215mg, 1.0 mmol).

¹H NMR (CDCl₃): δ 7.60 (br, 1H), 7.12 (s, 1H), 3.66 (s, 2H), 3.42 (m,2H), 3.29 (m, 4H), 2.93 (q, 2H), 2.56 (m, 4H), 1.60-1.99 (m, 16H), 1.36(t, 3H), 0.95-1.35 (m, 3H), 0.88 (d, 3H) ppm;

HPLC-MS: m/z 512 (M+1).

Example 384Trans-4-{2-[3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide

Prepared in 62% (326 mg) yield as described in general procedure (B)fromtrans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea(349 mg, 1.0 mmol) and piperazine-1-sulfonic acid dimethylamidehydrochloride (230 mg, 1 mmol).

¹H NMR (CDCl₃): δ 7.58 (br, 1H), 7.11 (s, 1H), 3.65 (s, 2H), 3.46 (m,2H), 3.25 (m, 4H), 2.82 (s, 6H), 2.52 (m, 4H), 1.01-1.99 (m, 19H), 0.89(d, 3H) ppm; HPLC-MS: m/z 527 (M+1).

Example 385Trans-3-(4-{2-[3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonyl)-propionicacid methyl ester

Prepared in 60% (342 mg) yield as described in general procedure (B)fromtrans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea(349 mg, 1.0 mmol) and4-(2-methoxycarbonyl-ethanesulfonyl)-piperazin-1-ium; chloride (273 mg,1.0 mmol).

¹H NMR (CDCl₃): δ 7.22 (br, 1H), 7.10 (s, 1H), 3.73 (s, 3H), 3.65 (s,2H), 3.41 (m, 2H), 3.28 (br, 4H), 3.23 (t, 2H), 2.83 (t, 2H), 2.54 (br,4H), 1.02-1.94 (m, 19H), 0.88 (d, 3H) ppm;

HPLC-MS: m/z 570 (M+1).

Example 386Trans-3-(4-{2-[3-Cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonyl)-propionicacid

Prepared in 80% (223 mg) yield as described in general procedure (F)fromtrans-3-(4-{2-[3-cyclohexyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonyl)-propionicacid methyl ester (285 mg, 0.5 mmol).

¹H NMR (DMSO-d₆): δ 7.08 (s, 1H), 6.78 (br, 1H), 3.55 (s, 2H), 3.31 (m,2H), 3.21 (t, 2H), 3.14 (br, 4H), 2.46 (t, 2H), 2.40 (br, 4H), 1.11-1.87(m, 19H), 0.84 (d, 3H) ppm; HPLC-MS: m/z 556 (M+1).

Example 387Trans-3-(4-{2-[3-cycloheptyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonyl)-propionicacid methyl ester

Prepared in 65% (380 mg) yield as described in general procedure (B)fromtrans-1-cycloheptyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea(364 mg, 1.0 mmol) and4-(2-methoxycarbonyl-ethanesulfonyl)-piperazin-1-ium chloride (273 mg, 1mmol).

¹H NMR (CDCl₃): δ 7.52 (br, 1H), 7.11 (s, 1H), 3.73 (s, 3H), 3.66 (s,2H), 3.44 (m, 2H), 3.28 (br, 4H), 3.22 (t, 2H), 2.81 (t, 2H), 2.55 (br,4H), 1.05-2.1 (m, 21H), 0.88 (d, 3H) ppm; HPLC-MS: m/z 584 (M+1).

Example 388Trans-3-(4-{2-[3-cycloheptyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonyl)-propionicacid

Prepared in 75% (214 mg) yield as described in general procedure (F)fromtrans-3-(4-{2-[3-cycloheptyl-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-sulfonyl)-propionicacid methyl ester (293 mg, 0.5 mmol).

¹H NMR (DMSO-d₆): δ 7.07 (br, 1H), 7.05 (s, 1H), 3.55 (s, 2H), 3.49 (br,2H), 3.21 (m, 2H), 3.14 (br, 4H), 2.431 (t, 2H), 2.41 (br, 4H),0.88-2.12 (m, 21H), 0.84 (d, 3H) ppm; HPLC-MS: m/z 570 (M+1).

Example 3893-(5-Bromo-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-fluoro-phenyl)-piperidin-4-yl]-urea

Prepared in 50% (241 mg) yield as described in general procedure (C)from cyclohexyl-[1-(2-fluoro-phenyl)-piperidin-4-yl]-amine (276 mg, 1.0mmol) and 5-bromo-thiazol-2-ylamine (179 mg, 1.0 mmol).

¹H NMR (CDCl₃): δ 8.12 (br, 1H), 7.25 (s, 1H), 6.95-7.09 (m, 4H), 3.83(m, 1H), 3.51 (d, 1H), 3.42 (br, 1H), 3.40 (t, 1H), 2.77 (t, 1H), 2.63(t, 1H), 1.68-2.21 (m, 10H), 1.17-1.41 (m, 2H) ppm; HPLC-MS: m/z 482(M+1).

Example 3903-(5-Bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-phenyl-cyclohexyl)-urea

Prepared in 50% (232 mg) yield as described in general procedure (C)from cyclohexyl-(4-phenyl-cyclohexyl)-amine (257 mg, 1.0 mmol) and5-bromo-thiazol-2-ylamine (179 mg, 1.0 mmol).

¹H NMR (CDCl₃): δ 8.20 (br, 1H), 7.06-7.25 (m, 6H), 3.68 (m, 1H), 3.42(m, 1H), 1.56-2.51 (m, 17H), 1.14-1.35 (m, 2H) ppm; HPLC-MS: m/z 463(M+1).

Example 3911,1-Dicyclohexyl-3-[5-(isopropylamino-methyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.30 mmol),isopropylamine (30 μL, 0.36 mmol) and sodium triacetoxyborohydride (101mg, 0.48 mmol) to afford 47 mg (42%) of the desired product afterpurification.

¹H NMR (CDCl₃):

7.12 (s, 1H), 4.54 (s, 2H), 3.94 (br, 1H), 3.42 (br, 1H), 3.04 (m, 1H),2.18 (m, 2H), 1.83 (m, 6H), 1.68 (m, 6H), 1.07-1.38 (m, 14H) ppm;HPLC-MS: m/z 379 (M+1).

Example 3921,1-Dicyclohexyl-3-(5-cyclopentylaminomethyl-thiazol-2-yl)-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol),cyclopentylamine (45 μL, 0.45 mmol) and sodium triacetoxyborohydride(102 mg, 0.48 mmol) to afford 45 mg (37%) of the desired product afterpurification.

¹H NMR (CDCl₃):

7.08 (s, 1H), 4.53 (s, 1H), 3.85 (s, 2H), 3.40 (br, 1H), 3.12 (m, 1H),2.60 (m, 2H), 1.49-1.75 (m, 8H), 1.78-1.98 (m, 8H), 1.04-1.36 (m, 14H)ppm; HPLC-MS: m/z 405 (M+1).

Example 3934-{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-benzoic acidmethyl ester

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (160 mg. 0.48 mmol),acetic acid (27 μL, 0.48 mmol), methyl 4-amino benzoate (144 mg, 0.95mmol) and sodium triacetoxyborohydride (303 mg, 1.43 mmol) to afford 106mg (47%) of the desired product after purification.

¹H NMR (CDCl₃):

8.17 (br, 1H), 7.86 (d, 2H), 7.23 (s, 1H), 6.60 (d, 2H), 4.47 (s, 3H),3.85 (m, 3H), 3.42 (m, 2H), 1.78-1.84 (m, 8H), 1.62-1.74 (m, 6H),1.24-1.38 (m, 4H), 1.10-1.22 (m, 2H) ppm; HPLC-MS: m/z 471 (M+1).

Example 394(4-{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-phenyl)-aceticacid ethyl ester

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.298 mmol),acetic acid (17 μL, 0.29 mmol), (4-amino-phenyl)-acetic acid ethyl ester(14 mg, 0.45 mmol) and sodium triacetoxyborohydride (101 mg, 0.48 mmol)to afford 43 mg (30%) of the desired product after purification.

¹H NMR (CDCl₃):

7.19 (s, 1H), 7.07 (d, 2H), 6.58 (d, 2H), 4.38 (br, 2H), 4.11 (q, 2H),3.47 (s, 2H), 3.40 (br, 1H), 1.77-1.86 (m, 8H), 1.60-1.74 (m, 6H),1.09-1.35 (m, 11H) ppm; HPLC-MS: m/z 499 (M+1).

Example 3954-({[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-methyl)-benzoicacid methyl ester

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (150 mg. 0.42 mmol),acetic acid (24 μL, 0.42 mmol), 4-aminomethyl-benzoic acid methyl ester(170 mg, 0.84 mmol) and sodium triacetoxyborohydride (268 mg, 1.27 mmol)to afford 74 mg (36%) of the desired product after purification.

HPLC-MS: m/z 485 (M+1).

Example 396{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-acetic acidmethyl ester

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (31 mg. 0.095 mmol),glycine methyl ester hydrochloride (24 mg, 0.20 mmol) and sodiumtriacetoxyborohydride (61 mg, 0.286 mmol) to afford 15 mg (39%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.14 (s, 1H), 3.93 (s, 2H), 3.72 (s, 3H), 3.42 (m, 3H), 3.00 (br, 1H),1.78-1.40 (m, 6H), 1.53-1.75 (m, 10H), 1.11-1.40 (m, 6H) ppm; HPLC-MS:m/z 409 (M+1).

Example 3971-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-2(R)-carboxylicacid benzyl ester

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (75 mg. 0.223 mmol),pyrrolidine-2(R)-carboxylic acid benzyl ester hydrochloride (73 mg, 0.31mmol) and sodium triacetoxyborohydride (71 mg, 0.335 mmol) to afford 92mg (78%) of the desired product after purification.

¹H NMR (CDCl₃):

7.49 (m, 2H), 7.37 (m, 3H), 7.04 (s, 1H), 5.16 (q, 2H), 4.54 (m, H),3.87 (dd, 2H), 3.39 (m, 3H), 3.08 (m, 1H), 2.85 (m, 1H), 2.61 (m, 1H),1.91-2.12 (m, 1H), 1.80-1.88 (m, 6H), 1.64-1.76 (m, 8H), 1.12-1.40 (m,6H) ppm; HPLC-MS: m/z 525 (M+1).

Example 3981-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-yl-methyl]-pyrrolidine-2(R)-carboxylicacid

1-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-2(R)-carboxylicacid benzyl ester (50 mg, 0.095 mmol) was combined with palladium oncarbon (25 mg) in MeOH. Vacuum was applied to degas the mixture. Thereaction was subjected to hydrogen and vigorous stirring until no estercould be detected (36 h). After filtering and concentration, 35 mg (84%)pure acid was obtained by trituration.

HPLC-MS: m/z 435 (M+1).

Example 3991,1-Dicyclohexyl-3-[5-(3-oxo-piperazin-1-ylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (40 mg, 0.12 mmol),2-piperazinone (18 mg, 0.18 mmol), acetic acid (7 μL, 0.12 mmol) andsodium triacetoxyborohydride (38 mg, 0.18 mmol) to afford 20 mg (40%) ofthe desired product after purification.

¹H NMR (CDCl₃):

7.14 (s, 1H), 6.35 (s, 1H), 4.62 (br, 1H), 3.72 (s, 2H), 3.43 (m, 2H),3.34 (m, 2H), 3.18 (s, 2H), 2.69 (m, 2H), 1.79-1.87 (m, 6H), 1.62-1.73(m, 6H), 1.12-1.39 (m, 8H) ppm; HPLC-MS: m/z 420 (M+1).

Example 4001,1-Dicyclohexyl-3-[5-(3-oxo-pyrazolidin-1-ylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (42 mg. 0.125 mmol),3-pyrazolidinone hydrochloride (23 mg, 0.188 mmol) and sodiumtriacetoxyborohydride (40 mg, 0.188 mmol) to afford 8 mg (16%) of thedesired product after purification.

¹H NMR (CDCl₃):

8.07 (s, 1H), 7.40 (s, 1H), 4.45 (m, 2H), 3.42 (m, 2H), 3.07 (m, 3H),2.89 (m, 2H), 2.19 (2H), 1.83 (m, 4H), 1.68 (6H), 1.12-1.40 (8H) ppm;HPLC-MS: m/z 406 (M+1).

Example 401{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-acetic acidtert-butyl ester

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol),glycine tert-butyl ester hydrochloride (50 mg, 0.30 mmol) and sodiumtriacetoxyborohydride (59 mg, 0.28 mmol) to afford 62 mg (68%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.14 (s, 1H), 3.91 (s, 2H), 3.43 (m, 2H), 3.30 (s, 2H), 2.68 (br, 1H),1.59-1.93 (m, 12H), 1.46 (s, 9H), 1.10-1.39 (m, 8H) ppm; HPLC-MS: m/z451 (M+1).

Example 402{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-acetic acid

{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-acetic acidtert-butyl ester (14 mg, 0.03 mmol) was dissolved in methylene chloride.Hydrogen chloride (100 μL, 4N in dioxane) was added and the reaction wasstirred at ambient temperature until no ester could be detected. Thereaction was diluted with diethyl ether and concentrated. The resultingresidue was dissolved in a minimum amount of methylene chloride,precipitated with diethyl ether and decanted. This was repeated toafford 9 mg (69%) of the desired compound. HPLC-MS: m/z 395 (M+1).

Example 4031-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-3-carboxylicacid benzyl ester

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol),pyrrolidine-3-carboxylic acid benzyl ester hydrochloride (50 mg, 0.25mmol) and sodium triacetoxyborohydride (55 mg, 0.26 mmol) to afford 52mg (50%) of the desired product after purification.

¹H NMR (CDCl₃):

7.34 (m, 5H), 7.11 (s, 1H), 5.12 (d, 2H), 3.74 (s, 2H), 3.42 (m, 2H),2.95-3.09 (m, 2H), 2.65-2.78 (m, 2H), 2.53 (m, 1H) 2.00-2.15 (m, 2H),1.61-1.88 (m, 12H), 1.10-1.37 (m, 8H) ppm; HPLC-MS: m/z 525 (M+1).

Example 4041-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-3-carboxylicacid

1-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-3-carboxylicacid benzyl ester (30 mg, 0.057 mmol) was combined with palladium oncarbon (20 mg) in MeOH. Vacuum was applied to degas the mixture. Thereaction was subjected to hydrogen and vigorous stirring until no estercould be detected (24 h). After filtering and concentration, the pureacid was obtained by trituration.

HPLC-MS: m/z 435 (M+1).

Example 4051,1-Dicyclohexyl-3-(5-morpholin-4-ylmethyl-thiazol-2-yl)-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.30 mmol),acetic acid (18 μL, 0.30 mmol), morpholine (78 μL, 0.90 mmol) and sodiumtriacetoxyborohydride (70 mg, 0.33 mmol) to afford 42 mg (34%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.02 (s, 1H), 3.70 (m, 4H), 3.62 (s, 2H), 3.44 (m, 2H), 2.48 (m, 4H),1.78-1.89 (m, 8H), 1.60-1.74 (m, 8H), 1.11-1.40 (m, 4H) ppm; HPLC-MS:m/z 407 (M+1).

Example 4064-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-morpholine-2-carboxylicacid

Prepared 11 mg (58%) following the general procedures (P) and (F) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (70 mg. 0.21 mmol) andmorpholine-2-carboxylic acid benzyl ester hydrochloride (77 mg, 0.30mmol).

HPLC-MS: m/z 451 (M+1).

Example 4071,1-Dicyclohexyl-3-(5-thiomorpholin-4-ylmethyl-thiazol-2-yl)-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (60 mg. 0.18 mmol),acetic acid (11 μL, 0.18 mmol), thiomorpholine (21 μL, 0.22 mmol) andsodium triacetoxyborohydride (38 mg, 0.20 mmol) to afford 7 mg (9%) ofthe desired product after purification.

¹H NMR (CDCl₃):

7.15 (s, 1H), 3.90 (m, 4H), 3.74 (s, 2H), 3.48 (m, 2H), 2.67 (m, 4H),1.79-1.92 (m, 8H), 1.62-1.77 (m, 8H), 1.12-1.42 (m, 4H) ppm; HPLC-MS:m/z 423 (M+1).

Example 4081,1-Dicyclohexyl-3-[5-(1,1-dioxo-thiomorpholin-4-ylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol),1,1-dioxo-thiomorpholine hydrochloride (52 mg, 0.30 mmol) and sodiumtriacetoxyborohydride (51 mg, 0.24 mmol) to afford 16 mg (18%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.12 (s, 1H), 3.76 (s, 2H), 3.42 (m, 2H), 3.03 (m, 8H), 1.78-1.96 (m,6H), 1.61-1.78 (m, 6H), 1.09-1.45 (m, 8H) ppm; HPLC-MS: m/z 455 (M+1).

Example 4091,1-Dicyclohexyl-3-[5-(4-oxo-piperidin-1-ylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (34 mg. 0.10 mmol),4-piperidone hydrochloride (46 mg, 0.30 mmol) and sodiumtriacetoxyborohydride (25 mg, 0.12 mmol) to afford 5 mg (12%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.99 (br, 1H), 7.11 (s, 1H), 3.91 (m, 2H), 3.74 (s, 2H), 3.42 (m, 2H),2.77 (m, 2H), 2.44 (m, 2H), 1.79-1.91 (m, 8H), 1.62-1.75 (m, 8H),1.09-1.41 (m, 4H) ppm; HPLC-MS: m/z 419 (M+1).

Example 4101,1-Dicyclohexyl-3-[5-(4-propionyl-piperazin-1-ylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (60 mg, 0.18 mmol),1-piperazinyl-1-propanone (39 mg, 0.22 mmol), catalytic acetic acid andsodium triacetoxyborohydride (47 mg, 0.22 mmol) to afford 12 mg (15%) ofthe desired product after purification.

HPLC-MS: m/z 463 (M+1).

Example 4114-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester

Prepared as described in general procedure P using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (1.0 g, 3.0 mmol),piperazine-1-carboxylic acid tert-butyl ester (838 mg, 4.5 mmol), aceticacid (40 μL, 0.6 mmol) and sodium triacetoxyborohydride (765 mg, 3.6mmol) to afford 835 mg (55%) of the desired product after purification.

¹H NMR (CDCl₃):

7.98 (br, 1H), 7.12 (s, 1H), 3.61 (s, 2H), 3.53 (m, 2H), 3.17 (m, 4H),2.46 (m, 4H), 1.58-1.92 (m, 12H), 1.47 (s, 9H), 1.07-1.44 (m, 8H) ppm;HPLC-MS: m/z 506 (M+1).

Example 4121,1-Dicyclohexyl-3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol),4-methanesulfonyl-piperazine hydrochloride (45 mg, 0.23 mmol) and sodiumtriacetoxyborohydride (40 mg, 0.19 mmol) to afford 28 mg (38%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.92 (br, 1H), 7.05 (s, 1H), 3.64 (s, 2H), 3.38 (m, 2H), 3.21 (m, 4H),2.76 (s, 3H), 2.58 (m, 4H), 1.76-1.84 (m, 6H), 1.60-1.72 (m, 6H),1.10-1.43 (m, 8H) ppm; HPLC-MS: m/z 484 (M+1).

Example 413 1,1-Dicyclohexyl-3-[5-(4-ethanesulfonyl-1-piperazinylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol),ethanesulfonyl-piperazine hydrochloride (128 mg, 0.60 mmol) and sodiumtriacetoxyborohydride (83 mg, 0.39 mmol) to afford 66 mg (44%) of thedesired product after purification.

¹H NMR (CDCl₃): δ 7.98 (br, 1H), 7.10 (s, 1H), 3.66 (s, 2H), 3.42 (m,2H), 3.29 (m, 4H), 2.94 (q, 2H), 2.56 (m, 4H), 1.65-1.92 (m, 12H),1.16-1.44 (m, 11H) ppm; HPLC-MS: m/z 498 (M+1).

Example 4141,1-Dicyclohexyl-3-{5-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-thiazol-2-yl}-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol),1-propanesulfonyl-piperazine hydrochloride (52 mg, 0.23 mmol) and sodiumtriacetoxyborohydride (48 mg, 0.23 mmol) to afford 21 mg (27%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.99 (s, 1H), 7.11 (s, 1H), 3.68 (s, 2H), 3.38 (m, 2H), 3.27 (m, 4H),2.89 (m, 2H), 2.55 (m, 4H), 1.77-1.91 (m, 8H), 1.48-1.76 (m, 10H),113-1.40 (m, 8H), 1.07 (t, 3H) ppm; HPLC-MS: m/z 512 (M+1).

Example 4151,1-Dicyclohexyl-3-{5-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thiazol-2-yl}-urea

Prepared as described in general procedure (Q) using1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-ureahydrochloride (36 mg, 0.08 mmol), DIEA (42 μL, 0.24 mmol) andpropane-2-sulfonyl chloride (18 μL, 0.16 mmol) to afford 18 mg (44%) ofthe desired product after purification.

¹H NMR (CDCl₃):

7.10 (s, 1H), 3.65 (s, 2H), 3.39 (m, 6H), 3.27 (m, 4H), 3.16 (m, 1H),2.52 (m, 4H), 1.59-1.96 (m, 12H), 1.04-1.40 (m, 14H) ppm; HPLC-MS: m/z512 (M+1).

Example 4163-{5-[4-(Butane-1-sulfonyl)-piperazin-1-ylmethyl]-thiazol-2-yl}-1,1-dicyclohexyl-urea

Prepared as described in general procedure (Q) using1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-ureahydrochloride (30 mg, 0.06 mmol), DIEA (32 μL, 0.18 mmol) andbutane-1-sulfonyl chloride (16 μL, 0.12 mmol) to afford 19 mg (61%) ofthe desired product after purification.

¹H NMR (CDCl₃):

7.13 (s, 1H), 3.63 (s, 2H), 3.42 (m, 2H), 3.28 (m, 4H), 2.88 (m, 2H),2.48 (m, 4H), 1.31-1.94 (m, 22H), 0.78-1.06 (m, 4H) ppm; HPLC-MS: m/z526 (M+1).

Example 4173-[5-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1,1-dicyclohexyl-urea

Prepared as described in general procedure (Q) using1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-ureahydrochloride (36 mg, 0.08 mmol), DIEA (42 μL, 0.24 mmol) andbenzenesulfonyl chloride (20 μL, 0.16 mmol) to afford 37 mg (68%) of thedesired product after purification.

¹H NMR (CDCl₃):

7.74 (d, 2H), 7.62 (m, 1H), 7.55 (m, 2H), 7.08 (s, 1H), 3.60 (s, 2H),3.41 (m, 2H), 3.00 (m, 4H), 2.55 (m, 4H), 1.78-1.86 (m, 8H), 1.63-1.72(m, 8H), 1.23-1.38 (m, 4H) ppm; HPLC-MS: m/z 546 (M+1).

Example 4181,1-Dicyclohexyl-3-[5-(4-phenylmethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (Q) using1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-ureahydrochloride (26 mg, 0.05 mmol), DIEA (26 μL, 0.15 mmol) andalpha-toluenesulfonyl chloride (20 mg, 0.10 mmol) to afford 8 mg (29%)of the desired product after purification.

¹H NMR (CDCl₃):

8.05 (br, 1H), 7.38 (m, 5H), 7.08 (s, 1H), 4.19 (s, 2H), 3.56 (s, 2H),3.43 (m, 2H), 3.12 (m, 4H), 2.43 (m, 4H), 1.77-1.88 (m, 6H), 1.56-1.75(m, 6H), 1.10-1.39 (m, 8H) ppm; HPLC-MS: m/z 560 (M+1).

Example 4191,1-Dicyclohexyl-3-{5-[4-(1-methyl-1H-imidazole-4-sulfonyl)-piperazin-1-ylmethyl]-thiazol-2-yl}-urea

Prepared as described in general procedure (Q) using1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-ureahydrochloride (27 mg, 0.055 mmol), DIEA (29 μL, 0.17 mmol) andN-methylimidazole-4-sulfonyl chloride (20 mg, 0.11 mmol) to afford 20 mg(66%) of the desired product after purification.

¹H NMR (CDCl₃):

8.04 (br, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.09 (s, 1H), 3.90 (m, 1H),3.79 (s, 3H), 3.73 (s, 2H), 3.42 (m, 2H), 3.15 (m, 4H), 2.56 (m, 4H),1.44-1.91 (m, 12H), 1.08-1.44 (m, 6H), 0.86 (m, 2H) ppm; HPLC-MS: m/z550 (M+1).

Example 420 Propane-2-sulfonic acid{1-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylmethyl]-piperidin-4-yl}-amide

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (21 mg, 0.07 mmol),propane-2-sulfonic acid piperidin-4-yl amide hydrochloride (17 mg, 0.077mmol) and sodium triacetoxyborohydride (19 mg, 0.09 mmol) to afford 4 mg(11%) of the desired product after purification.

HPLC-MS: m/z 526 (M+1).

Example 4214-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-piperazine-1-sulfonicacid dimethylamide

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (84 mg, 0.25 mmol),piperazine-1-sulfonic acid dimethyl amide hydrochloride (115 mg, 0.50mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) to afford 54mg (42%) of the desired product after purification.

¹H NMR (CDCl₃):

7.09 (s, 1H), 3.64 (s, 2H), 3.42 (m, 2H), 3.25 (m, 4H), 2.81 (s, 6H),2.51 (m, 4H), 1.77-1.91 (m, 6H), 1.61-1.73 (m, 6H), 1.09-1.41 (m, 8H)ppm; HPLC-MS: m/z 513 (M+1).

Example 4224-[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (176 mg, 0.50mmol), piperazine carboxylic acid tert-butyl ester (140 mg, 0.75 mmol),and HBTU (285 mg, 0.75 mmol) were weighed out and added to a 25 mLreaction flask. DMF (5 mL) and DIEA (175 μL, 1.0 mmol) were added. Thereaction was stirred under nitrogen at ambient temperature overnight.The reaction was diluted with EtOAc (10 mL) and quenched with saturatedaqueous NH₄Cl (10 mL). After separation and extraction with EtOAc (2×5mL) the combined organic portions were dried over MgSO₄. Purificationwith silica gel and 10% EtOAc in CH₂Cl₂ afforded 187 mg (72%) of thedesired compound.

¹H NMR (CDCl₃):

8.08 (s, 1H), 7.67 (s, 1H), 3.70 (m, 4H), 3.18 (m, 6H), 1.63-1.89 (m,14H), 1.48 (s, 9H), 1.12-1.39 (m, 6H) ppm; HPLC-MS: m/z 520 (M+1).

Example 4234-[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carbonyl]-piperazine-1-sulfonicacid dimethylamide

2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (53 mg, 0.15mmol), piperazine sulfonic acid dimethylamide hydrochloride (44 mg, 0.19mmol), and HBTU (74 mg, 0.19 mmol) were weighed out and added to a 10 mLreaction flask. DMF (1.5 mL) and DIEA (65 μL, 0.38 mmol) were added. Thereaction was stirred under nitrogen at ambient temperature overnight.The reaction was diluted with EtOAc (5 mL) and quenched with saturatedaqueous NH₄Cl (5 mL). After separation and extraction with EtOAc (2×5mL) the combined organic portions were dried over MgSO₄. Purificationwith silica gel (10% EtOAc and 1% MeOH in CH₂Cl₂) afforded 53 mg (67%)of the desired compound.

¹H NMR (CDCl₃):

8.13 (br, 1H), 7.67 (s, 1H), 3.80 (m, 4H), 3.46 (m, 2H), 3.30 (m, 4H),2.86 (s, 6H), 1.62-1.93 (m, 14H), 1.13-1.42 (m, 6H) ppm; HPLC-MS: m/z527 (M+1).

Example 424{1-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidin-3-yl}-sulfonicacid dimethylamide

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (40 mg, 0.12 mmol),pyrrolidine-3-amino sulfonic acid dimethylamide hydrochloride (34 mg,0.15 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to afford36 mg (59%) of the desired product after purification.

¹H NMR (CDCl₃):

8.31 (br, 1H), 7.21 (s, 1H), 5.69 (br, 1H), 3.87 (m, 1H), 3.70 (m, 2H),3.40 (m, 2H), 2.90 (m, 1H), 2.76 (s, 6H), 2.55 (m, 1H), 2.25 (m, 2H),1.61-1.93 (m, 16H), 1.10-1.41 (m, 6H) ppm; HPLC-MS: m/z 513 (M+1).

Example 425 Ethanesulfonic acid{1-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidin-3-yl}-amide

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol),ethanesulfonic acid pyrrolidin-3-yl amide hydrochloride (41 mg, 0.19mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 35mg (47%) of the desired product after purification.

¹H NMR (CDCl₃):

8.46 (br, 1H), 7.23 (s, 1H), 6.22 (br, 1H), 3.96 (m, 1H), 3.69 (s, 2H),3.39 (m, 2H), 3.00 (q, 2H), 2.93 (m, 1H), 2.76 (1H), 2.56 (1H),2.21-2.34 (m, 2H), 1.60-1.95 (m, 19H), 1.33 (t, 3H), 1.18 (m, 2H) ppm;HPLC-MS: m/z 498 (M+1).

Example 4261,1-Dicyclohexyl-3-{5-[(1-ethanesulfonyl-pyrrolidin-3-ylamino)-methyl]-thiazol-2-yl}-urea

Prepared as described in general procedure (P) using1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol),3-amino-1-pyrrolidine ethane sulfonamide hydrochloride (41 mg, 0.19mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 15mg (20%) of the desired product after purification.

¹H NMR (CDCl₃):

8.28 (br, 1H), 7.13 (s, 1H), 4.63 (m, 1H), 3.89 (s, 2H), 3.37-3.62 (m,6H), 3.17 (m, 1H), 3.03 (m, 3H), 2.09 (m, 2H), 1.63-1.88 (m, 12H), 1.39(t, 3H). 1.12-1.38 (m, 6H) ppm; HPLC-MS: m/z 498 (M+1).

Example 4274-[3-(5-Formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester

Prepared in a manner similar to general procedure (C) using5-formyl-2-aminothiazole (1.88 g, 14.6 mmol),4-(4-methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butylester (4.32 mg, 14.6 mmol), catalytic DMAP, CDI (2.60 g, 1.1 mmol) andTHF with heating to 65° C. afforded 1.77 g (27%) of the desired productafter purification.

¹H NMR (CDCl₃):

9.91 (s, 1H), 8.01 (s, 1H), 3.74 (m, 1H), 3.33 (m, 1H), 2.75 (m, 4H),2.04 (m, 4H), 1.53-1.82 (m, 8), 1.46 (s, 9H), 1.62-1.83 (m, 4H),0.85-1.15 (m, H) ppm; HPLC-MS: m/z 451 (M+1).

Example 4284-[3-[5-(4-Ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester

Prepared as described in general procedure (P) using4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester (200 mg, 0.45 mmol), piperazine ethane sulfonamidehydrochloride (125 mg, 0.58 mmol), triethyl amine (80 μL, 0.58 mmol) andsodium triacetoxyborohydride (113 mg, 0.53 mmol) to afford 160 mg (58%)of the desired product after purification.

¹H NMR (CDCl₃):

9.37 (br, 1H), 7.16 (s, 1H), 4.21 (m, 2H), 3.70 (s, 2H), 3.35 (m, 5H),2.96 (m, 2H), 2.79 (m, 2H), 2.61 (m, 4H), 1.82-2.21 (m, 6H), 1.63 (m,6H), 1.47 (s, 9H), 1.38 (m, 4H), 1.05 (d, 3H), 0.92 (m, 1H) ppm;HPLC-MS: m/z 613 (M+1).

Example 4291-(1-Cyclopentanecarbonyl-piperidin-4-yl)-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (N) using3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-1-piperidin-4-yl-ureahydrochloride (48 mg, 0.078 mmol), TEA (24 μL, 0.17 mmol) andcyclopentane carbonylchloride (11 μL, 0.086 mmol) and to afford 19 mg(40%) of the desired product after purification.

¹H NMR (CDCl₃):

8.22 (br, 1H), 7.10 (s, 1H), 4.78 (m, 1H), 4.07 (m, 1H), 3.68 (m, 3H),3.31 (m, 4H), 2.97 (m, 3H), 2.56 (m, 4H), 2.14 (m, 2H), 1.45-2.05 (m,21H), 1.37 (t, 3H), 0.87-1.10 (m, 4H) ppm; HPLC-MS: m/z 609 (M+1).

Example 4303-[5-(4-Ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-[1-(4-fluoro-benzoyl)-piperidin-4-yl]-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (N) using3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-1-piperidin-4-yl-ureahydrochloride (46 mg, 0.075 mmol), TEA (26 μL, 0.19 mmol) and4-fluorobenzoyl chloride (10 μL, 0.083 mmol) and to afford 41 mg (86%)of the desired product after purification.

¹H NMR (CDCl₃):

8.07 (s, 1H), 7.45 (m, 2H), 7.11 (m, 3H), 3.86 (m, 1H), 3.65 (s, 2H),3.32 (m, 5H), 2.73-3.13 (m, 6H), 2.55 (m, 4H), 2.38 (m, 2H), 1.99 (m,2H), 1.48-1.87 (m, 8H), 1.37 (t, 3H), 0.90-1.13 (m, 4H) ppm; HPLC-MS:m/z 635 (M+1).

Example 4314-[3-[5-(4-Dimethylsulfamoyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester

Prepared as described in general procedure (P) using4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester (202 mg, 0.45 mmol), piperazine sulfonic aciddimethylamide hydrochloride (132 mg, 0.58 mmol), triethyl amine (80 μL,0.58 mmol) and sodium triacetoxyborohydride (118 mg, 0.53 mmol) toafford 110 mg (39%) of the desired product after purification.

¹H NMR (CDCl₃):

8.43 (br, 1H), 7.11 (s, 1H), 4.24 (m, 2H), 3.65 (m, 3H), 3.26 (m, 4H),2.82 (s, 6H), 2.74 (m, 2H), 2.52 (m, 4H), 2.08 (m, 2H), 1.57-2.03 (m,8H), 1.49 (s, 9H), 1.26 (m, 2H), 1.05 (d, 3H), 0.82-0.97 (m, 2H) ppm;HPLC-MS: m/z 628 (M+1).

Example 4324-{2-[3-(1-Cyclopentanecarbonyl-piperidin-4-yl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide

Prepared as described in general procedure (N) using4-{2-[3-(4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide hydrochloride (50 mg, 0.088 mmol), TEA (31 μL, 0.22mmol) and cyclopentane carbonyl chloride (13 μL, 0.11 mmol) to afford 27mg (49%) of the desired product after purification.

¹H NMR (CDCl₃):

8.62 (br, 1H), 7.10 (s, 1H), 4.78 (d, 1H), 4.07 (d, 1H), 3.76 (m, 1H),3.65 (s, 2H), 3.27 (m, 4H), 3.05 (m, 1H), 2.91 (m, 1H), 2.82 (s, 6H),2.53 (m, 4H), 1.38-2.19 (m, 21H), 1.05 (d, 3H), 0.81-0.98 (m, 2H) ppm;HPLC-MS: m/z 624 (M+1).

Example 4334-{2-[3-[1-(4-Fluoro-benzoyl)-piperidin-4-yl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide

Prepared as described in general procedure (N) using4-{2-[3-(4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide hydrochloride (47 mg, 0.083 mmol), TEA (26 μL, 0.19mmol) and 4-fluorobenzoyl chloride (10 μL, 0.083 mmol) to afford 39 mg(73%) of the desired product after purification.

¹H NMR (CDCl₃):

8.17 (br, 1H), 7.46 (m, 2H), 7.10 (m, 3H), 4.82 (m, 1H), 3.73 (m, 1H),3.65 (s, 2H), 3.27 (m, 5H), 3.03 (m, 1H), 2.82 (s, 6H), 2.53 (m, 4H),2.32 (m, 2H), 2.00 (m, 2H), 1.36-1.87 (m, 6H), 1.15 (m, 4H), 1.05 (d,3H), 0.80-0.99 (m, 1H) ppm; HPLC-MS: m/z 650 (M+1).

Example 434 TTP-00212496{4-[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carbonyl]-piperazin-1-yl}-aceticacid ethyl ester

2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (53 mg, 0.15mmol), 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (39 mg, 0.23 mmol),and HBTU (74 mg, 0.19 mmol) were weighed out and added to a 25 mLreaction flask. DMF (2 mL) and DIEA (52 μL, 0.30 mmol) were added. Thereaction was stirred under nitrogen at ambient temperature overnight.The reaction was diluted with EtOAc (10 mL) and quenched with saturatedaqueous NH₄Cl (10 mL). After separation and extraction with EtOAc (2×5mL) the combined organic portions were dried over MgSO₄. Purificationwith silica gel chromatography (10% EtOAc and 1% MeOH in CH₂Cl₂)afforded 37 mg (49%) of the desired compound.

HPLC-MS: m/z 506 (M+1).

Example 435{4-[2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carbonyl]-piperazin-1-yl}-aceticacid

Prepared as described in general procedure (F) using{4-[2-(3,3-dicyclohexyl-ureido)-thiazole-5-carbonyl]-piperazin-1-yl}-aceticacid ethyl ester (16 mg, 0.32 mmol) afforded 6 mg (39%) of the desiredcompound.

HPLC-MS: m/z 478 (M+1).

Example 4361,1-Dicyclohexyl-3-{5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-thiazol-2-yl}-urea

2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (53 mg, 0.15mmol), 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (42 mg, 0.19 mmol),and HBTU (71 mg, 0.19 mmol) were weighed out and added to a 25 mLreaction flask. DMF (2 mL) and DIEA (65 μL, 0.37 mmol) were added. Thereaction was stirred under nitrogen at ambient temperature overnight.The reaction was diluted with EtOAc (10 mL) and quenched with saturatedaqueous NH₄Cl (10 mL). After separation and extraction with EtOAc (2×5mL) the combined organic portions were dried over MgSO₄. Purificationwith silica gel chromatography (10% EtOAc and 1% MeOH in CH₂Cl₂)afforded 17 mg (31%) of the desired compound.

¹H NMR (CDCl₃):

8.26 (br, 1H), 7.65 (s, 1H), 3.82 (s, 2), 3.65 (m, 8H), 3.33 (m, 6H),2.58 (m, 4H), 1.59-2.17 (m, 12H), 1.12-1.20 (m, 6H), 0.80-0.92 (m, 2H)ppm; HPLC-MS: m/z 547 (M+1).

Example 4374-[3-{5-[4-(2-Methoxycarbonyl-acetyl)-piperazin-1-ylmethyl]-thiazol-2-yl}-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester

Prepared as described in general procedure (P) using4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid tert-butyl ester (68 mg, 0.15 mmol),3-oxo-3-piperazin-1-yl-propionic acid methyl ester hydrochloride (54 mg,0.19 mmol) and sodium triacetoxyborohydride (38 mg, 0.18 mmol) to afford23 mg (25%) of the desired product after purification.

HPLC-MS: m/z 621 (M+1).

Example 4383-(4-{2-[3-(1-Butyryl-piperidin-4-yl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazin-1-yl)-3-oxo-propionicacid methyl ester

Prepared as described in general procedure (N) using3-(4-{2-[3-(4-Methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylmethyl}-piperazin-1-yl)-3-oxo-propionicacid methyl ester hydrochloride (17 mg, 0.032 mmol), TEA (10 μL, 0.050mmol) and 1-butyryl chloride (5 μL, 0.039 mmol) to afford 12 mg (65%) ofthe desired product after purification.

¹H NMR (CDCl₃):

8.67 (br, 1H), 7.08 (s, 1H), 4.76 (m, 1H), 3.94 (m, 1H), 3.74 (s, 3H),3.63 (m, 4H), 3.45 (s, 2H), 3.41 (m, 2H), 3.30 (m, 1H), 3.07 (m, 1H),2.56 (m, 1H), 2.46 (m, 4H), 2.32 (t, 2H), 2.12 (m, 2H), 1.93 (m, 2H),1.53-1.81 (m, 6H), 1.46 (m, 2H), 1.24 (m, 4H), 1.05 (m, 2H), 0.98 (t,3H), 0.79-0.94 (m, 1H) ppm; HPLC-MS: m/z 591 (M+1).

Example 4391-Cycloheptyl-3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (P) using1-cycloheptyl-3-(5-formyl-thiazol-2-yl)-1-(4-trans-methyl-cyclohexyl)-urea(100 mg, 0.28 mmol), ethane sulfonyl piperazine hydrochloride (68 mg,0.30 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) to afford18 mg (13%) of the desired product after purification.

¹H NMR (CDCl₃):

7.89 (br, 1H), 7.11 (s, 1H), 3.78 (m, 1H), 3.66 (s, 2H), 3.41 (m, 2H),3.29 (m, 4H), 2.93 (m, 3H), 2.55 (m, 4H), 2.08 (m, 2H), 1.46-1.83 (m,12H), 1.37 (t, 3H), 1.20-1.35 (m, 2H), 1.08 (m, 2H), 0.90 (d, 3H), 0.82(m, 1H) ppm; HPLC-MS: m/z 526 (M+1).

Example 4404-{2-[3-Cycloheptyl-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonicacid dimethylamide

Prepared as described in general procedure (P) using1-cycloheptyl-3-(5-formyl-thiazol-2-yl)-1-(4-trans-methyl-cyclohexyl)-urea(100 mg, 0.28 mmol), piperazine sulfonic acid dimethyl amidehydrochloride (69 mg, 0.30 mmol) and sodium triacetoxyborohydride (70mg, 0.33 mmol) to afford 16 mg (11%) of the desired product afterpurification.

HPLC-MS: m/z 541 (M+1).

Example 4411-Cycloheptyl-3-(5-hydroxymethyl-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea

Prepared using1-cycloheptyl-3-(5-formyl-thiazol-2-yl)-1-(4-trans-methyl-cyclohexyl)-urea(20 mg, 0.055 mmol) and lithium borohydride (45 μL, 2M in THF) in MeOH(1 mL). Purification without work-up (silica gel, 10% EtOAc and 2% MeOHin CH₂Cl₂) afforded 20 mg (99%) of the desired compound.

¹H NMR (CDCl₃):

8.90 (br, 1H), 7.18 (s, 1H), 4.73 (s, 2H), 3.73 (br, 1H), 3.43 (m, 1H),2.07 (m, 2H), 1.65-1.83 (m, 8H), 1.43-1.65 (m, 7H), 1.21-1.43 (m, 2H),0.99-1.14 (m, 2H), 0.90 (d, 3H), 0.85-0.89 (m, 1H) ppm; HPLC-MS: m/z 366(M+1).

Example 442 1,1-Dicyclohexyl-3-(5-hydroxymethyl-thiazol-2-yl)-urea

Prepared using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg,0.15 mmol) and lithium borohydride (95 μL, 2M in THF) in MeOH (1 mL).Purification without work-up (silica gel, 10% EtOAc and 2% MeOH inCH₂Cl₂) afforded 49 mg (97%) of the desired compound.

¹H NMR (CDCl₃):

8.12 (br, 1H), 7.19 (s, 1H), 4.73 (s, 2H), 3.45 (m, 2H), 1.60-2.07 (m,12H), 1.09-1.42 (m, 8H) ppm; HPLC-MS: m/z 338 (M+1).

Example 443{[2-(3,3-Dicyclohexyl-ureido)-thiazole-4-carbonyl]-amino}-acetic acidmethyl ester

Prepared in 30% yield (76 mg) as described in general procedure (K) from2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.6 mmol)and glycine methyl ester (HCl salt, 75 mg, 0.6 mmol).

¹H NMR (CDCl₃): δ 8.06 (s, 1H), 7.65 (s, 1H), 4.24 (d, 2H), 3.80 (s,3H), 3.46 (m, 2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 423 (M+1).

Example 4441,1-Dicyclohexyl-3-[4-(morpholine-4-carbonyl)thiazol-2-yl]-urea

Prepared in 24% yield (61 mg) as described in general procedure (K) from2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.60mmol) and morpholine (52 mg, 0.60 mmol).

¹H NMR (d6-DMSO): δ 8.10 (s, 1H), 7.65 (s, 1H), 3.60 (m, 4H), 3.20 (m,4H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 421 (M+1).

Example 4452(S)-{[2-(3,3-Dicyclohexylureido)-thiazole-4-carbonylamino)propionicacid methyl ester

Prepared in 17% yield (44 mg) as described in general procedure (K) from2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.60mmol) and (S)-alanine methyl ester (HCl salt, 84 mg, 0.6 mmol).

¹H NMR (CDCl₃): δ 8.00 (s, 1H), 7.62 (s, 1H), 4.79 (q, 1H), 3.78 (s,3H), 3.46 (m, 2H), 1.60-1.90 (m, 14H), 1.52 (d, 3H), 1.10-1.40 (m, 6H)ppm; HPLC-MS: m/z 437 (M+1).

Example 4462(S)-{[2-(3,3-Dicyclohexylureido)-thiazole-4-carbonyl]-amino}propionicacid

Prepared in 94% yield (36 mg) as described in general procedure (K).Hydrolysis of2(S)-{[2-(3,3-dicyclohexylureido)-thiazole-4-carbonyl]-amino}propionicacid methyl ester (40 mg, 0.09 mmol).

¹H NMR (4:1 CDCl₃-CD₃OD): δ 8.00 (s, 1H), 7.62 (s, 1H), 4.66 (m, 1H),3.44 (m, 2H), 1.60-1.90 (m, 14H), 1.55 (d, 3H), 1.10-1.40 (m, 6H) ppm;HPLC-MS: m/z 423 (M+1).

Example 447 2-{[2-(3,3-Dicyclohexylureido)-thiazole-4-carbonyl]aceticacid

Prepared in 95% yield (56 mg) as described in general procedure (F) byhydrolysis of2-{[2-(3,3-dicyclohexylureido)-thiazole-4-carbonyl]-amino}acetic acidmethyl ester (60 mg, 0.14 mmol).

¹H NMR (4:1 CDCl₃-CD₃OD): δ 8.06 (s, 1H), 7.65 (s, 1H), 7.54 (t, 1H),4.17 (d, 2H), 3.37 (m, 2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 409(M+1).

Example 4481,1-Dicyclohexyl-3-[4-(pyridin-2-yloxymethyl)-thiazol-4-yl]urea

1,1-Dicyclohexyl-3-(4-hydroxymethylthiazole-2-yl)urea (180 mg, 0.5 mmol)was dissolved in 5.0 mL anhydrous DMF and treated with NaH (60 mg, 1.50mmol) for 30 min at r.t. After addition of 2-bromopyridine (70 uL, 0.75mmol), the resulting solution was heated for 12 h at 95 C. After coolingto r.t., the DMF solution was diluted with 20 mL water and extractedwith EtOAc (2×20 mL). The combined organic extracts were washed withwater (2×10 mL), dried over sodium sulfate and concentrated to a yellowoil. After flash chromatography, the desired product was obtained in 25mg (11.5%) yield.

¹H NMR (d6-DMSO): δ 10.80 (s, 1H), 8.16 (d, 1H), 7.68 (m, 1H), 6.96 (m,2H), 6.82 (d, 1H), 5.20 (s, 2H), 3.40 (m, 2H), 1.15-1.90 (m, 20H) ppm;HPLC-MS: m/z 415 (M+1).

Example 4491,1-Dicyclohexyl-3-[4-(pyridin-2-yloxymethyl)-thiazol-4-yl]urea

Prepared in quantitative yield (1.85 g) as described in generalprocedure (F) by hydrolysis of[2-(3,3-dicyclohexylureido)-thiazol-4-yl]acetic acid ethyl ester (2.0 g,5.1 mmol).

¹H NMR (4:1 CDCl₃-CD₃OD): δ 6.60 (s, 1H), 3.46 (m, 4H), 1.15-1.90 (m,20H) ppm; HPLC-MS: m/z 366 (M+1).

Example 450{{[2-(3,3-Dicyclohexyl-ureido)-thiazol-4-ylmethyl]-carbamoyl}-methyl}carbamicacid tert-butyl ester

Prepared in 29% yield (40 mg) as described in general procedure (K) from3-(4-aminomethylthiazol-2-yl)-1,1-dicyclohexyl-urea (96 mg, 0.28 mmol)and Boc-glycine (60 mg, 0.30 mmol).

¹H NMR (CDCl₃): δ 6.80 (s, 1H), 6.60 (s, 1H), 4.29 (d, 2H), 3.83 (m,2H), 3.43 (s, 1H), 2.80 (s, 2H), 1.15-1.90 (m, 20H), 1.10 (s, 9H) ppm;HPLC-MS: m/z 494 (M+1).

Example 451 TTP-002033461,1-Dicyclohexyl-3-(4-morpholin-4-ylmethyl-thiazol-2-yl)-urea

1,1-Dicyclohexyl-3-(4-morpholin-4-ylmethyl-thiazol-2-yl)-urea wasprepared in 30% yield (30 mg) as described in general procedure A from1,1-dicyclohexyl-3-(4-formyl-thiazol-2-yl)-urea (101 mg, 0.3 mmol) andmorpholine (30 uL, 0.3 mmol) using sodium triacetoxyborohydride as thereducing reagent.

HPLC-MS: m/z 407 (M+1).

Example 4521,1-Dicyclohexyl-3-{4-[2-(pyridin-2-yloxy)-ethyl]-thiazol-2-yl}-urea

1,1-Dicyclohexyl-3-{4-[2-(pyridin-2-yloxy)-ethyl]-thiazol-2-yl}-urea wasprepared from the sodium salt of1,1-dicyclohexyl-3-[4-(2-hydroxyethyl)-thiazol-2-yl]-urea (50 mg, 0.14mmol; 0.5 mmol NaH, DMF as solvent) and 2-bromopyridine (20 mg, 0.14mmol). After aqueous workup, the resulting oil was purified on silicagel to give1,1-dicyclohexyl-3-{4-[2-(pyridin-2-yloxy)-ethyl]-thiazol-2-yl}-urea in20 mg (33%) yield.

¹H NMR (CDCl₃): δ 8.08 (d, 1H), 7.49 (t, 1H), 6.80 (t, 1H), 6.67 (d,1H), 6.47 (s, 1H), 4.50 (t, 2H), 3.38 (m, 2H), 3.10 (t, 2H), 1.10-1.90(m, 20H) ppm; HPLC-MS: m/z 429 (M+1).

Example 4532-[2-(3,3-Dicyclohexylureido)-thiazol-4-ylmethylsulfanyl)-1H-imidazole-4-carboxylicacid

2-[2-(3,3-Dicyclohexylureido)-thiazol-4-ylmethylsulfanyl)-1H-imidaole-4-carboxylicacid ethyl ester was prepared in 20% yield as described in generalprocedure L from 1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester. The ester (30 mg,0.06 mmol) was hydrolysed using general procedure F to give2-[2-(3,3-dicyclohexylureido)-thiazol-4-ylmethylsulfanyl)-1H-imidaole-4-carboxylicacid in 80% yield (22 mg).

HPLC-MS: m/z 464 (M+1).

Example 4543-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acid

3-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acidwas prepared in 40% yield as described in general procedure F from3-{[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acidmethyl ester, which in turn was prepared in 21% yield as described ingeneral procedure H using2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid and methyl-3-aminobenzoate.

HPLC-MS: m/z 471 (M+1).

Example 455 4-[2-(3,3-Dicyclohexylureideo)-thiazole-5-ylsulfanyl]benzoicacid methyl ester

Prepared in 20% yield (47 mg) as described in general procedure (E)using 3-(5-bromothiazol-2-yl)-1,1-bis-4-methylcyclohexyl)urea and4-mercapto-benzoic acid methyl ester.

¹H NMR (CDCl₃): δ 8.10 (s, 1H), 7.89 (d, 2H), 7.54 (s, 1H), 7.21 (d,2H), 3.89 (s, 3H), 3.43 (m, 2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z474 (M+1).

Example 456 4-[2-(3,3-Dicyclohexylureideo)-thiazole-5-ylsulfanyl]benzoicacid

Prepared in 85% yield (24 mg) as described in general procedure (F) from4-[2-(3,3-dicyclohexylureideo)-thiazole-5-ylsulfanyl]benzoic acid methylester (30 mg, 0.06 mmol).

¹H NMR (d6-DMSO): δ 7.83 (d, 2H), 7.67 (s, 1H), 7.22 (d, 2H), 3.60 (m,2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 460 (M+1).

Example 457{4-[2-(3,3-Dicyclohexylureideo)-thiazole-5-ylsulfanyl]-phenyl}-aceticacid methyl ester

Prepared in 15% yield (37 mg) as described in general procedure (E)using 3-(5-bromothiazol-2-yl)-1,1-bis-4-methylcyclohexyl)urea and4-mercaptobenzeneacetic acid methyl ester.

¹H NMR (CDCl₃): δ 8.00 (s, 1H), 7.49 (s, 1H), 7.21 (d, 1H), 7.19 (d,1H), 7.16 (d, 1H), 7.13 (d, 1H), 3.67 (s, 3H), 3.55 (s, 2H), 3.42 (m,2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 488 (M+1).

Example 458{4-[2-(3,3-Dicyclohexylureideo)-thiazole-5-ylsulfanyl]-phenyl}-aceticacid

Prepared in 90% yield (18 mg) as described in general procedure (F) from{4-[2-(3,3-dicyclohexylureideo)-thiazole-5-ylsulfanyl]-phenyl}-aceticacid methyl ester (21 mg, 0.04 mmol).

¹H NMR (d6-DMSO): δ 7.49 (s, 1H), 7.18 (d, 2H), 7.14 (d, 2H), 3.50 (s,2H), 3.32 (m, 2H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z 474 (M+1).

Example 4593-{2-[3-Cyclohexyl-3-(4-trans-methylcyclohexyl)-ureido]-thiazol-5-yl}-acrylicacid ethyl ester

A solution ofcyclohexyl-(trans-4-methylcylcohexyl)-3-(5-formyl-thiazol-2-yl)-urea(350 mg, 1.00 mmol) and (carbethoxymethylene)triphenylphosphorane (420mg, 1.20 mmol) in THF (5 mL) was stirred at 50° C. for 12 h. Thereaction mixture was concentrated and the residue was purified by flashchromatography (silica, CH₂Cl₂-EtOAc, 4:1) to obtain3-{2-[3-cyclohexyl-3-(4-trans-methylcyclohexyl)-ureido]-thiazol-5-yl}-acrylicacid ethyl ester (300 mg) in 73% yield.

¹H NMR (CDCl₃): δ 8.20 (s, 1H), 7.70 (d, 1H), 7.47 (s, 1H), 6.06 (d,1H), 4.23 (q, 2H), 3.40 (m, 2H), 1.50-2.00 (m, 12H), 1.40-1.50 (m, 2H),1.30 (t, 3H), 1.0-1.20 (M, 5H), 0.91 (d, 3H) ppm; HPLC-MS: m/z 420(M+1).

Example 4603-{2-[3-Cyclohexyl-3-(4-trans-methylcyclohexyl)-ureido]-thiazol-5-yl}-propionicacid

3-{2-[3-Cyclohexyl-3-(4-trans-methylcyclohexyl)-ureido]-thiazol-5-yl}-acrylicacid ethyl ester (200 mg, 0.48 mmol) was reduced with hydrogen (60 psi,pressure reaction vessel) over Pd/C (300 mg) to give3-{2-[3-cyclohexyl-3-(4-trans-methylcyclohexyl)-ureido]-thiazol-5-yl}-propionicacid ethyl ester (110 mg) after purification (silica gel, 20% ethylacetate in hexanes).

3-{2-[3-Cyclohexyl-3-(4-trans-methylcyclohexyl)-ureido]-thiazol-5-yl}-propionicacid ethyl ester (100 mg) was hydrolysed according to general procedureF using NaOH to give 85 mg (91% yield) of3-{2-[3-cyclohexyl-3-(4-trans-methylcyclohexyl)-ureido]-thiazol-5-yl}-propionicacid.

¹H NMR (d6-DMSO): δ 6.94 (s, 1H), 4.4 (t, 2H), 3.6 (m, 2H), 2.80 (t,2H), 1.10-1.90 (m, 19H), 0.85 (d, 3H) ppm; HPLC-MS: m/z 394 (M+1).

Example 461 2-(3,3-Dicyclohexylureido)-thiazole-5-carboxylicacid-(2-methanesulfonylethyl)amide

Prepared in 75% yield (170 mg) as described in general procedure (H)from 2-(3,3-dicyclohexylureido)thiazole-5-carboxylic acid (175 mg, 0.5mmol) and 2-aminoethylmethylsulfone (HCl salt, 80 mg, 0.5 mmol).

¹H NMR (CDCl₃): δ 7.83 (s, 1H), 7.77 (d, 1H), 3.88 (t, 2H), 3.70 (t,2H), 3.67 (m, 2H), 2.90 (s, 3H), 1.10-1.90 (m, 20H) ppm; HPLC-MS: m/z457 (M+1).

Example 4622-[3-Cyclohexyl-3-(4-methylcyclohexyl)-ureido]-thiazole-5-carboxylicacid methyl ester

Prepared in 69% yield (8.3 g) as described in general procedure (C) fromcyclohexyl-(4-methylcyclohexyl)-amine (6.2 g, 32 mmol) andmethyl-2-aminothiazole-5-carboxylate (5.0 g, 31.6 mmol).

¹H NMR (CDCl₃): δ 8.00 (s, 1H), 3.82 (s, 3H), 3.36 (m, 2H), 1.15-2.00(m, 19H), 1.02 (d, 3H) ppm; HPLC-MS: m/z 380 (M+1).

Example 463{2-[3-Cyclohexyl-3-(4-phenyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester

Prepared in 60% (292 mg) yield as described in general procedure (D)from 3-(5-bromothiazol-2-yl)-1-cyclohexyl-1-(4-phenyl-cyclohexyl)-urea(463 mg, 1.0 mmol) and methylthioglycolate (212 mg, 2.0 mmol).

¹H NMR (CDCl₃): δ 8.16 (br, 1H), 7.42 (s, 1H), 7.18-7.38 (m, 5H), 3.71(s, 3H), 3.56 (br, 1H), 3.44 (br, 1H), 3.43 (s, 2H), 2.58 (m, 1H),1.17-2.02 (m, 18H) ppm; HPLC-MS: m/z 488 (M+1).

Example 464{2-[3-Cyclohexyl-3-(4-phenyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared in 80% (190 mg) yield as described in general procedure (F)from{2-[3-cyclohexyl-3-(4-phenyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester (244 mg, 0.5 mmol).

¹H NMR (CDCl₃): δ 12.02 (br, 1H), (8.32 (br, 1H), 7.14-7.39 (m, 6H),3.45 (m, 4H), 2.19 (m, 1H), 1.07-1.96 (m, 18H) ppm; HPLC-MS: m/z 474(M+1).

Example 4651,1-Bis-(1-acetyl-piperidin-4-yl)-3-(5-bromo-thiazol-2-yl)-urea

Prepared in 65% (76 mg) yield as described in general procedure (N) from3-(5-bromothiazol-2-yl)-1,1-di-piperidin-4-yl-urea (97 mg, 0.25 mmol)and acetyl chloride (78 mg, 1 mmol).

¹H NMR (CDCl₃): δ 7.38 (br, 1H), 7.19 (s, 1H), 4.76 (m, 4H), 3.90 (m,4H), 3.55 (m, 2H), 3.17 (m, 2H), 2.61 (m, 2H), 2.17 (m, 2H), 2.10 (s,3H), 2.06 (s, 3H), 1.34 (m, 2H) ppm; HPLC-MS: m/z 473 (M+1).

Example 4661-Cycloheptyl-3-(5-formylthiazol-2-yl)-1-(trans-4-methylcyclohexyl)urea

2-Amino-5-formylthiazole (2.56 g, 20.0 mmol), carbonyldiimidazole (3.25g, 20.0 mmol) and a catalytic amount of DMAP were heated together in 60mL THF at 50° C. for 3 h. To this solution was addedcycloheptyl-(trans-4-methylcyclohexyl)amine (4.18 g, 20.0 mmol) and thereaction mixture was stirred for an additional 6 h at room temperature.The reaction mixture was concentrated and the crude product was purifiedby flash chromatography (silica, CH₂Cl₂-EtOAc, 4:1) to obtain1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (2.3 g, 31% yield).

HPLC-MS: m/z 364 (M+1).

Example 4671-(1-Butyryl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-cycloheptyl-urea

Prepared as described in general procedure (G) using4-cycloheptylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z 427 (M+1).

Example 468[2-(3-Cycloheptyl-3-cyclopentyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid

[2-(3-Cycloheptyl-3-cyclopentyl-ureido)-thiazol-5-ylsulfanyl]-aceticacid ethyl ester prepared as described in general procedures (A) and (B)using cycloheptyl-cyclopentylamine and 5-aminothiazole-2-mercaptoaceticacid ethyl ester. Hydrolysis using general procedure (F) gave the titlecompound.

HPLC-MS: m/z 398 (M+1).

Example 469[2-(3-Cyclobutyl-3-cycloheptyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

[2-(3-Cycloheptyl-3-cyclobutyl-ureido)-thiazol-5-ylsulfanyl]-acetic acidethyl ester prepared as described in general procedures (A) and (B)using cycloheptyl-cyclobutylamine and 5-aminothiazole-2-mercaptoaceticacid ethyl ester. Hydrolysis using general procedure (F) gave the titlecompound.

HPLC-MS: m/z 384 (M+1).

Example 470{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester prepared as described in general procedures (A) and (B)using cyclobutyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 384 (M+1).

Example 4713-(5-Chloro-thiazol-2-yl)-1-cycloheptyl-1-(1-ethanesulfonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cycloheptanone and 2-amino-5-chlorothiazole

HPLC-MS: m/z 449 (M+1).

Example 472{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-yl]-methyl-amino}-acetic acidethyl ester

Prepared as described in general procedure (A) using dicyclohexylamineand [(2-aminothiazol-5-yl)-methyl-amino]-acetic acid ethyl ester

HPLC-MS: m/z 867 (2M+Na).

Example 4733-[2-(3-Cyclobutyl-3-cycloheptyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid

[2-(3-Cycloheptyl-3-cyclobutyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid ethyl ester prepared as described in general procedure (A) usingcycloheptyl-cyclobutylamine and 5-aminothiazole-2-mercaptoacetic acidethyl ester. Hydrolysis using general procedure (F) gave the titlecompound

HPLC-MS: m/z 398 (M+1).

Example 4743-[2-(3-Cycloheptyl-3-cyclopentyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid

[2-(3-Cycloheptyl-3-cyclopentyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid ethyl ester pre-pared as described in general procedure (A) usingcycloheptyl-cyclopentylamine and 5-aminothiazole-2-mercaptoacetic acidethyl ester. Hydrolysis using general procedure (F) gave the titlecompound

HPLC-MS: m/z 412 (M+1).

Example 4753-(5-Chloro-thiazol-2-yl)-1-(1-cyclobutanecarbonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-chlorothiazole

HPLC-MS: m/z 439 (M+1).

Example 4763-(5-Chloro-thiazol-2-yl)-1-(1-cyclopentanecarbonyl-piperidin-4-yl)-1-(trans-4-methylcyclohexyl)-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-chlorothiazole

HPLC-MS: m/z 453 (M+1).

Example 4773-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-(1-pentanoyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-chlorothiazole

HPLC-MS: m/z 442 (M+1).

Example 478 2-(3,3-Dicyclohexyl-ureido)-thiazole-5-sulfonic acid(2-dimethylamino-ethyl)-amide

Prepared as described in Example 173 using dicyclohexylamine,N-acetamino-5-thiazolesulfonyl chloride and 2-dimethylaminoethylamine.

HPLC-MS: m/z 458 (M+1).

Example 479 2-(3,3-Dicyclohexyl-ureido)-thiazole-5-sulfonic acid(2-diethylamino-ethyl)-amide

Prepared as described in Example 173 using dicyclohexylamine,N-acetamino-5-thiazolesulfonyl chloride and 2-diethylaminoethylamine.

HPLC-MS: m/z 486 (M+1).

Example 480 2-(3,3-Dicyclohexyl-ureido)-thiazole-5-sulfonic acid(2-morpholin-4-yl-ethyl)-amide

Prepared as described in Example 173 using dicyclohexylamine,N-acetamino-5-thiazolesulfonyl chloride and 1-(2-aminoethyl)piperidine.

HPLC-MS: m/z 501 (M+1).

Example 4811-Cyclohexyl-1-(trans-4-hydroxy-cyclohexyl)-3-thiazol-2-yl-urea

Reaction of[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-cyclohexyl-amineand 2-aminothiazole using general procedure (A) gave1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1-cyclohexyl-3-thiazol-2-yl-urea.Removal of the silyl protection group by addition oftetrabutylammoniumchloride (1.1 equiv) in THF for 1 h at roomtemperature followed by flash chromatography afforded the titlecompound.

HPLC-MS: m/z 324 (M+1).

Example 4821,1-Dicyclohexyl-3-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland 2-diethylamino-ethanethiol

HPLC-MS: m/z 439 (M+1).

Example 4831,1-Dicyclohexyl-3-[5-(3-dimethylamino-propylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland 3-dimethylamino-1-propylchloride.

HPLC-MS: m/z 425 (M+1).

Example 4841,1-Dicyclohexyl-3-[5-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland 2-chloromethyl-2-imidazoline.

HPLC-MS: m/z 422 (M+1).

Example 4853-[5-(2-Azepan-1-yl-ethylsulfanyl)-thiazol-2-yl]-1,1-dicyclohexyl-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland 2-(hexamethyleneimino)ethylchloride

HPLC-MS: m/z 465 (M+1).

Example 4863-(5-Chloro-thiazol-2-yl)-1-cycloheptyl-1-(1-phenylmethanesulfonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cycloheptanone and 2-amino-5-chlorothiazole

HPLC-MS: m/z 511 (M+1).

Example 4871-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-methanesulfonyl-thiazol-2-yl)-urea

Prepared by oxidising1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-urea(Example 339) using montmorillonite clay, oxone (2.5 equivalents) for 16h at room temperature in dichloromethane. The title compound waspurified by HPLC.

HPLC-MS: m/z 430 (M+1).

Example 4881,1-Dicyclohexyl-3-[4-methyl-5-(2-morpholin-4-yl-ethanesulfonyl)-thiazol-2-yl]-urea

Prepared by oxidising1,1-Dicyclohexyl-3-[4-methyl-5-(2-morpholin-4-yl-ethanesulfanyl)-thiazol-2-yl]-urea(Example 309) using montmorillonite clay, oxone (2.5 equivalents) for 16h at room temperature in dichloromethane. The title compound waspurified by HPLC.

HPLC-MS: m/z 500 (M+1).

Example 4891,1-Dicyclohexyl-3-[4-methyl-5-(2-piperidin-1-yl-ethanesulfonyl)-thiazol-2-yl]-urea

Prepared by oxidising1,1-Dicyclohexyl-3-[4-methyl-5-(2-piperidin-1-yl-ethanesulfonyl)-thiazol-2-yl]-urea(Example 302) using montmorillonite clay, oxone (2.5 equivalents) for 16h at room temperature in dichloromethane. The title compound waspurified by HPLC.

HPLC-MS: m/z 498 (M+1).

Example 490{2-[3-Cyclohexyl-3-(6-oxo-piperidin-3(S)-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-Cyclohexyl-3-(6-oxo-piperidin-3(S)-yl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester was prepared as described in general procedures (A) and(B) using 5-cyclohexylamino-piperidin-2-one and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 413 (M+1).

Example 4911,1-Dicyclohexyl-3-(5-ethenesulfonyl-4-methyl-thiazol-2-yl)-urea

A secondary product prepared by oxidising Example 309 usingmontmorillonite clay, oxone (2.5 equivalents) for 16 h at roomtemperature in dichloromethane. The title compound was purified by HPLC.

HPLC-MS: m/z 412 (M+1).

Example 492(2-{3-Cyclohexyl-3-[1-(thiophene-2-carbonyl)-pyrrolidin-3(R)-yl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

Prepared in an identical manner to Example 271 using3(R)-amino-1-Boc-pyrrolidine.

HPLC-MS: m/z 495 (M+1).

Example 4933-(5-Chloro-thiazol-2-yl)-1-cycloheptyl-1-[1-(propane-1-sulfonyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cycloheptanone and 2-amino-5-chlorothiazole

HPLC-MS: m/z 463 (M+1).

Example 4943-(5-Chloro-thiazol-2-yl)-1-cycloheptyl-1-(1-cyclopentanecarbonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cycloheptanone and 2-amino-5-chlorothiazole

HPLC-MS: m/z 453 (M+1).

Example 4953-[2-(3-Cyclohexyl-3-indan-2-yl-ureido)-thiazol-5-ylsulfanyl]-propionicacid

Prepared in an identical manner to Example 342 using indane,cyclohexanone and 5-aminothiazol-2-mercaptopropionic acid ethyl ester

HPLC-MS: m/z 446 (M+1).

Example 4963-{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester prepared as described in general procedure (A) usingcyclobutyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 398 (M+1).

Example 4973-{2-[3-Cyclopentyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

{2-[3-Cyclopentyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester prepared as described in general procedure (A) usingcyclopentyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 412 (M+1).

Example 4983-{2-[3-Cycloheptyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

{2-[3-Cycloheptyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester prepared as described in general procedure (A) usingcycloheptyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 440 (M+1).

Example 4993-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z 411 (M+1).

Example 5003-(5-Chloro-thiazol-2-yl)-1-(1-cyclobutanecarbonyl-piperidin-4-yl)-1-cyclohexyl-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z 447 (M+1).

Example 5013-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-cyclopropyl-acetyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z 447 (M+1).

Example 5024-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-piperidin-1-yl}-4-oxo-butyricacid

Prepared as described in general procedure (G) using4-cyclohexylamino-piperidine-1-carboxylic acid tert-butyl ester and5-chloro-2-aminothiazole

HPLC-MS: m/z 443 (M+1).

Example 5031,1-Dicyclohexyl-3-{5-[2-(1H-tetrazol-5-yl)-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared as described in general procedure (H) using1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritoland 5-(2-chloroethyl)-1H-tetrazole.

HPLC-MS: m/z 437 (M+1).

Example 5041-(1-Acetyl-piperidin-3-yl)-3(S)-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea

Prepared as described in general procedures (A) and (B). using1-(3(S)-cyclohexylamino-piperidin-1-yl)-ethanone and5-chloro-2-aminothiazole

HPLC-MS: m/z 385 (M+1).

Example 505{2-[3-(1-Acetyl-piperidin-3(S)-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-(1-Acetyl-piperidin-3(S)-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester prepared as described in general procedures (A) and(B). using 1-(3(S)cyclohexylamino-piperidin-1-yl)-ethanone and(2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 441 (M+1).

Example 5063-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(4,4-difluoro-cyclohexyl)-urea

Prepared using general procedures (A) and (B) usingcyclohexyl-(4,4-difluoro-cyclohexyl)-amine and 5-chloro-2-aminothiazole

HPLC-MS: m/z 378 (M+1).

Example 5073-(5-Chloro-thiazol-2-yl)-1-(1-cyclopropanecarbonyl-piperidin-4-yl)-1-(trans-4-methylcyclohexyl)-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-chlorothiazole

HPLC-MS: m/z 425 (M+1).

Example 5081-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-[5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)pyrrolidine.

HPLC-MS: m/z 480 (M+1).

Example 5091-(1-Acetyl-piperidin-4-yl)-3-[5-(2-azepan-1-yl-ethylsulfanyl)-thiazol-2-yl]-1-cyclohexyl-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-(hexamethyleneimino)ethylchloride

HPLC-MS: m/z 508 (M+1).

Example 5101-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-diethylamino-ethanethiol

HPLC-MS: m/z 482 (M+1).

Example 5111-(1-Acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)piperidine

HPLC-MS: m/z 508 (M+1).

Example 5121-(1-Acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)pyrrolidine

HPLC-MS: m/z 494 (M+1).

Example 5131-(1-Acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)morpholine

HPLC-MS: m/z 510 (M+1).

Example 5141-(1-Acetyl-piperidin-4-yl)-3-[5-(2-azepan-1-yl-ethylsulfanyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-(hexamethyleneimino)ethylchloride

HPLC-MS: m/z 522 (M+1).

Example 5151-(1-Acetyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-indan-2-yl-urea

Prepared as described in general procedures (A) and (B) using indane,N-acetylpiperidin-4-one and 5-chloro-2-aminothiazole.

HPLC-MS: m/z 419 (M+1).

Example 516{2-[3-(1-Acetyl-piperidin-4-yl)-3-indan-2-yl-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-(1-Acetyl-piperidin-4-yl)-3-indan-2-yl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester was prepared as described in general procedures (A) and(B) using indane, N-acetylpiperidin-4-one and5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound

HPLC-MS: m/z 475 (M+1).

Example 517{2-[3-Cyclohexyl-3-(4,4-difluoro-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-Cyclohexyl-3-(4,4-difluoro-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester prepared using general procedures (A) and (B) usingcyclohexyl-(4,4-difluoro-cyclohexyl)-amine and5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 434 (M+1).

Example 5181-Cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-1-[1-(thiophene-2-carbonyl)-pyrrolidin-3(R)-yl]-urea

Prepared as described in general procedure (H) using1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(thiophene-2-carbonyl)-pyrrolidin-3(R)-yl]-urea,dithioerythritol and methyliodide.

HPLC-MS: m/z 451 (M+1).

Example 5191-Cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)morpholine

HPLC-MS: m/z 468 (M+1).

Example 5201-Cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)piperidine

HPLC-MS: m/z 466 (M+1).

Example 5213-[5-(2-Azepan-1-yl-ethylsulfanyl)-thiazol-2-yl]-1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-(hexamethyleneimino)ethyl chloride.

HPLC-MS: m/z 480 (M+1).

Example 5223-{2-[3-(1-Acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

3-{2-[3-(1-Acetyl-piperidin-4-yl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester prepared as described in general procedures (A) and (B)using 1-[4-(4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and3-(2-amino-thiazol-5-ylsulfanyl)propionic acid ethyl ester. Hydrolysisusing general procedure (F) gave the title compound.

HPLC-MS: m/z 469 (M+1).

Example 5233-{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester prepared as described in general procedure (A) usingcyclohexyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 426 (M+1).

Example 5243-[2-(3-Cyclohexyl-3-cyclopentyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid

{2-[3-Cyclopentyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester prepared as described in general procedure (A) usingcyclopentyl-(trans-4-methyl-cyclohexyl)-amine and5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 398 (M+1).

Example 5253-(5-Chloro-thiazol-2-yl)-1-cycloheptyl-1-(1-propionyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cycloheptanone and 2-amino-5-chlorothiazole

HPLC-MS: m/z 413 (M+1).

Example 5263-(5-Chloro-thiazol-2-yl)-1-cycloheptyl-1-(1-methanesulfonyl-piperidin-4-yl)-urea

Prepared as described in general procedure (G) using3-amino-1-Boc-piperidine, cycloheptanone and 2-amino-5-chlorothiazole

HPLC-MS: m/z 435 (M+1).

Example 5271-Cyclohexyl-3-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-chlorotriethylamine

HPLC-MS: m/z 454 (M+1).

Example 5281-Cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-[5-(3-morpholin-4-yl-propylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 4-(3-chloropropyl)morpholine

HPLC-MS: m/z 482 (M+1).

Example 5291-(1-Acetyl-piperidin-4-yl)-3-[5-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 3-chloroethyl-2-imidazoline.

HPLC-MS: m/z 479 (M+1).

Example 5301-(1-Acetyl-piperidin-4-yl)-3-[5-(3-amino-propylsulfanyl)-thiazol-2-yl]-1-(trans-4-methylcyclohexyl)-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 3-chloropropylamine

HPLC-MS: m/z 454 (M+1).

Example 531{2-[3-Cyclopentyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedure (F) from{2-[3-cyclopentyl-3-(4-trifluoromethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester.

HPLC-MS: m/z 452 (M+1).

Example 5321,1-Dicyclohexyl-3-[5-(2-oxo-2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

To Example 55 (0.1 mmol) in 2 mL dimethylformamide was added 1.2equivalents of DHOBt and 1 equivalent of EDAC. After stirring for 1 h, 1equivalent of piperidine and 1 equivalent of diisopropylethylamine wasadded. The reaction was diluted with 10 ml of EtOAc and 5 ml of 10%NaHSO₄, mixed and separated. The organic phase was washed with 3 ml ofwater, 3 ml of sat. NaHCO₃, 3 ml of brine, dried (MgSO₄), filtered andconcentrated in vacuo. Purification by HPLC gave the title compound.

HPLC-MS: m/z 465 (M+1).

Example 5331,1-Dicyclohexyl-3-[5-(2-morpholin-4-yl-2-oxo-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared in a similar manner to Example 532 using morpholine.

HPLC-MS: m/z 467 (M+1).

Example 5342-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-N,N-diethyl-acetamide

Prepared in a similar manner to Example 532 using diethylamine.

HPLC-MS: m/z 453 (M+1).

Example 5354-{2-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetyl}-piperazine-1-carboxylicacid tert-butyl ester

Prepared in a similar manner to Example 532 usingtert-butyl-1-piperazine carboxylate.

HPLC-MS: m/z 566 (M+1).

Example 536N-Benzyl-2-[2-(3,3-dicyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetamide

Prepared in a similar manner to Example 532 using benzylamine.

HPLC-MS: m/z 487 (M+1).

Example 5371-(1-Butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)morpholine

HPLC-MS: m/z 539 (M+1).

Example 5383-[5-(2-Azepan-1-yl-ethylsulfanyl)-thiazol-2-yl]-1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (H) and (I) using1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-(hexamethyleneimino)ethylchloride

HPLC-MS: m/z 452 (M+2).

Example 5391-(1-Butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)pyrrolidine.

HPLC-MS: m/z 525 (M+2).

Example 5401-(1-Butyryl-piperidin-4-yl)-3-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (H) and (I) using1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and 2-diethylamino-ethanethiol

HPLC-MS: m/z 526 (M+2).

Example 5411-(1-Butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-methylsulfanyl-thiazol-2-yl)-urea

Prepared as described in general procedures (H) and (I) using1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and iodomethane.

HPLC-MS: m/z 441 (M+2).

Example 5421-[1-(2-Cyclopropyl-acetyl)-piperidin-4-yl]-1-(trans-4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-methylthiazole

HPLC-MS: m/z 419 (M+1).

Example 5431-(1-Acetyl-pyrrolidin-3(S)-yl)-1-cyclohexyl-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(acetyl)-pyrrolidin-3(S)-yl]-urea,dithioerythritol and N-(2-chloroethyl)morpholine

HPLC-MS: m/z 482 (M+1).

Example 5441-(1-Acetyl-pyrrolidin-3(R)-yl)-1-cyclohexyl-3-[5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(acetyl)-pyrrolidin-3(R)-yl]-urea,dithioerythritol and N-(2-chloroethyl)pyrrolidine.

HPLC-MS: m/z 466 (M+1).

Example 5451-(trans-4-Methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-1-[1-(3,3,3-trifluoro-propionyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-methylthiazole

HPLC-MS: m/z 447 (M+1).

Example 546{2-[3-Cyclohexyl-3-(trans-4-hydroxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared in a similar manner to Example 381 using[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-cyclohexyl-amineand 5-aminothiazole-2-mercaptoacetic acid ethyl ester.

HPLC-MS: m/z 414 (M+1).

Example 5473-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(trans-4-hydroxy-cyclohexyl)-urea

Prepared in a similar manner to Example 381 using[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-cyclohexyl-amineand 5-chloro 2-aminothiazole.

HPLC-MS: m/z 358 (M+1).

Example 548{2-[3-Cyclohexyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

Prepared as described in general procedures (A) and (B) and (F) usingtrans-4-methoxy-cyclohexyl]-cyclohexyl-amine and5-aminothiazole-2-mercaptoacetic acid ethyl ester.

HPLC-MS: m/z 428 (M+1).

Example 5491-Cycloheptyl-3-[5-(2-diethylamino-ethylsulfanyl)-4-methyl-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (H) using dithioerythritoland N-(2-chloroethyl)morpholine

HPLC-MS: m/z 481 (M+1).

Example 5501-Cycloheptyl-1-(trans-4-methyl-cyclohexyl)-3-[4-methyl-5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using dithioerythritoland N-(2-chloroethyl)pyrrolidine

HPLC-MS: m/z 479 (M+1).

Example 5511-Cycloheptyl-1-(trans-4-methyl-cyclohexyl)-3-[4-methyl-5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using dithioerythritoland N-(2-chloroethyl)piperidine

HPLC-MS: m/z 493 (M+1).

Example 5523-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-[1-(3,3,3-trifluoro-propionyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-chlorothiazole

HPLC-MS: m/z 467 (M+1).

Example 5533-(5-Chloro-thiazol-2-yl)-1-[1-(2-cyclopropyl-acetyl)-piperidin-4-yl]-1-(4-methyl-cyclohexyl)-urea

Prepared as described in general procedure (G) using4-(trans-4-methyl-cyclohexylamino)-piperidine-1-carboxylic acidtert-butyl ester and 2-amino-5-chlorothiazole

HPLC-MS: m/z 439 (M+1).

Example 5544-[3-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid dimethylamide

To a solution of3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea(0.8 mmol), prepared as described in general procedure (G), steps 1-3,and 1.2 equivalents of DIPEA in 10 mL dioxane was addeddimethylcarbamoyl chloride (1.2 equivalents) in 1 ml dioxane. Thereaction was stirred overnight at room temperature, concentrated invacuo and purified by flash chromatography to give the title compound.

HPLC-MS: m/z 428 (M+1).

Example 555 2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazole-5-sulfonicacid (1-methyl-piperidin-4-yl)-amide

Prepared in a similar manner to Example 173 using dicyclohexylamine and4-methyl-thiazole-5-sulfonic acid (1-methyl-piperidin-4-yl)-amide

HPLC-MS: m/z 499 (M+1).

Example 5564-[3-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-ureido]-piperidine-1-sulfonicacid dimethylamide

Prepared in a similar manner to Example 554 using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand dimethylsulfamoyl chloride

HPLC-MS: m/z 464 (M+1).

Example 5573-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-[1-(propane-1-sulfonyl)-piperidin-4-yl]-urea

Prepared in a similar manner to Example 554 using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand propanesulfonylchloride

HPLC-MS: m/z 463 (M+1).

Example 5583-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-urea

Prepared in a similar manner to Example 554 using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand 4-morpholinecarbonyl chloride

HPLC-MS: m/z 470 (M+1).

Example 559N-(4-{4-[3-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-ureido]-piperidine-1-sulfonyl}-phenyl)-acetamide

Prepared in a similar manner to Example 554 using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand N-acetylsulfanilyl chloride.

HPLC-MS: m/z 554 (M+1).

Example 5601,1-Dicyclohexyl-3-{5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared in a similar manner to Example 532 using 1-benzylpiperazine.

HPLC-MS: m/z 480 (M+1).

Example 5613-{5-[2-(4-Benzyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-1,1-dicyclohexyl-urea

Prepared in a similar manner to Example 532 using 1-benzylpiperazine.

HPLC-MS: m/z 556 (M+1).

Example 5621,1-Dicyclohexyl-3-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared in a similar manner to Example 532 using 1-phenylpiperazine.

HPLC-MS: m/z 542 (M+1).

Example 5631,1-Dicyclohexyl-3-{5-[2-oxo-2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared in a similar manner to Example 532 using1-(2-pyrimidinyl)-piperazine.

HPLC-MS: m/z 544 (M+1).

Example 5641,1-Dicyclohexyl-3-{5-[2-oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared in a similar manner to Example 532 using1-(2-pyridinyl)-piperazine.

HPLC-MS: m/z 543 (M+1).

Example 5651,1-Dicyclohexyl-3-{5-[2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared in a similar manner to Example 532 using1-(4-pyridinyl)-piperazine.

HPLC-MS: m/z 543 (M+1).

Example 5661,1-Dicyclohexyl-3-{5-[2-(4-cyclopentyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared in a similar manner to Example 532 using1-cyclopentyl-piperazine

HPLC-MS: m/z 534 (M+1).

Example 5671,1-Dicyclohexyl-3-(5-{2-oxo-2-[4-(tetrahydro-furan-2-ylmethyl)-piperazin-1-yl]-ethylsulfanyl}-thiazol-2-yl)-urea

Prepared in a similar manner to Example 532 using1-(2-tetrahydrofurfuryl)-piperazine

HPLC-MS: m/z 550 (M+1).

Example 5681,1-Dicyclohexyl-3-{5-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-urea

Prepared in a similar manner to Example 532 using 1-ethyl-piperazine

HPLC-MS: m/z 494 (M+1).

Example 5694-[3-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylicacid diethylamide

Prepared in a similar manner to Example 554 using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand diethylcarbamoyl chloride

HPLC-MS: m/z 456 (M+1).

Example 5703-[2-(3-Cycloheptyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid

[2-(3-Cycloheptyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionicacid ethyl ester pre-pared as described in general procedure (A) usingcycloheptyl-cyclohexylamine and 5-aminothiazole-2-mercaptoacetic acidethyl ester. Hydrolysis using general procedure (F) gave the titlecompound

HPLC-MS: m/z 426 (M+1).

Example 5711-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-[5-(2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedures (H) and (I) using1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)piperidine

HPLC-MS: m/z 494 (M+1).

Example 5721-Cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and N-(2-chloroethyl)pyrrolidine

HPLC-MS: m/z 452 (M+1).

Example 5731,1-Dicyclohexyl-3-[5-(2-oxo-2-piperazin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea

To Example 55 (0.1 mmol) in 2 mL dimethylformamide was added 1.2equivalents of DHOBt and 1 equivalent of EDAC. After stirring for 1 h, 1equivalent of piperazine and 1 equivalent of diisopropylethylamine wasadded. The reaction was diluted with 10 ml of EtOAc and 5 ml of 10%NaHSO₄, mixed and separated. The organic phase was washed with 3 ml ofwater, 3 ml of sat. NaHCO₃, 3 ml of brine, dried (MgSO₄), filtered andconcentrated in vacuo. Purification by HPLC gave the title compound.

HPLC-MS: m/z 466 (M+1).

Example 5743-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-[1-(piperidine-1-carbonyl)-piperidin-4-yl]-urea

Prepared in a similar manner to Example 554 using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand 1-piperidinecarbonyl chloride

HPLC-MS: m/z 468 (M+).

Example 5753-{2-[3-Cyclohexyl-3-(4,4-difluoro-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Reaction of Boc-aminocyclohexanone with DAST in DCM for 24 h at roomtemperature gave (4,4-Difluoro-cyclohexyl)-carbamic acid tert-butylester after flash chromatography. Boc deprotection using TFA followed byreductive amination with cyclohexanone using general procedure B gavecyclohexyl-(4,4-difluoro-cyclohexyl)-amine. Treatment with CDI and5-aminothiazol-2-mercaptopropionic acid ethyl ester using generalprocedure (A) gave3-{2-[3-Cyclohexyl-3-(4,4-difluoro-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester, which was hydrolysed using general procedure (F) togive the title compound.

HPLC-MS: m/z 448 (M+1).

Example 5763-(5-Chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-[1-(propane-1-sulfonyl)-piperidin-4-yl]-urea

Prepared as described in general procedure (G) using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand 3-chloropropane-1-sulfonyl chloride

HPLC-MS: m/z 463 (M+1).

Example 5771-(1-Acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-fluoro-thiazol-2-yl)-urea

Prepared as described in general procedures (A) and (B) using1-(4-cyclohexylamino-piperidin-1-yl)-ethanone and5-fluoro-2-aminothiazole.

HPLC-MS: m/z 391 (M+23).

Example 578 1,1-Dicyclohexyl-3-(5-fluoro-thiazol-2-yl)-urea

Prepared as described in general procedures (A) and (B) usingdicyclohexylamine and 5-fluoro-2-aminothiazole.

HPLC-MS: m/z 326 (M+1).

Example 5791-Cyclohexyl-3-(5-fluoro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-(trans-4-methyl-cyclohexyl)-amine and5-fluoro-2-aminothiazole

HPLC-MS: m/z 340 (M+1).

Example 5803-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-1-(3-cyano-cyclohexyl)-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-(3-cyanocyclohexyl)-amine and 5-chloro-2-aminothiazole

HPLC-MS: m/z 367 (M+).

Example 5816-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-piperidin-1-yl}-6-oxo-hexanoicacid

Prepared as described in general procedure (G) using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand adipic acid.

HPLC-MS: m/z 471 (M+).

Example 582 1-Cyclohexyl-1-(2-methyl-cyclohexyl)-3-thiazol-2-yl-urea

Prepared as described in general procedures (A) and (B) usingcyclohexyl-(2-methylcyclohexyl)-amine and 2-aminothiazole

HPLC-MS: m/z 322 (M+).

Example 5835-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-piperidin-1-yl}-5-oxo-pentanoicacid

Prepared as described in general procedure (G) using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand glutaric acid

HPLC-MS: m/z 457 (M+).

Example 5842-{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and ethyl-2-bromopropionate.

HPLC-MS: m/z 428 (M+1).

Example 5857-{4-[3-(5-Chloro-thiazol-2-yl)-1-cyclohexyl-ureido]-piperidin-1-yl}-7-oxo-heptanoicacid

Prepared as described in general procedure (G) using3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-ureaand pimelic acid.

HPLC-MS: m/z 485 (M+).

Example 586(2-{3-(trans-4-Methyl-cyclohexyl)-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid

(2-{3-(trans-4-Methyl-cyclohexyl)-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-ureido}-thiazol-5-ylsulfanyl)-aceticacid ethyl ester was prepared in a similar manner to Example 554 using{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester and 4-morpholinecarbonyl chloride. Hydrolysis usinggeneral procedure (F) gave the title compound HPLC-MS: m/z 526 (M+).

Example 5872-{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionicacid

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and ethyl-2-bromo-2-methyl propionate.

HPLC-MS: m/z 441 (M+1).

Example 5881-{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-cyclobutanecarboxylicacid

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and ethyl-1-bromocyclobutane carboxylate.

HPLC-MS: m/z 453 (M+1).

Example 589{2-[3-(1-Dimethylsulfamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-(1-Dimethylsulfamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester was prepared in a similar manner to Example 554 using{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester and dimethylsulfamoyl chloride. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 520 (M+1).

Example 590{2-[3-(1-Dimethylcarbamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

{2-[3-(1-Dimethylcarbamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester was prepared in a similar manner to Example 554 using{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-aceticacid ethyl ester and dimethylcarbamoyl chloride. Hydrolysis usinggeneral procedure (F) gave the title compound.

HPLC-MS: m/z 484 (M+1).

Example 5912-{2-[3-Cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-3-methyl-butyricacid

Prepared as described in general procedure (H) using1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea,dithioerythritol and ethyl-2-bromoisovalerate.

HPLC-MS: m/z 455 (M+1).

Example 592 1,1-Dicyclohexyl-3-(5-methylsulfanyl-pyrazin-2-yl)-urea

Prepared as described in general procedures (A) and (B) usingdicyclohexylamine and 5-methylsulfanyl-pyrazin-2-ylamine

HPLC-MS: m/z 349 (M+).

Example 5934-[2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazole-5-sulfonylamino]-piperidine-1-carboxylicacid ethyl ester

Prepared as described in Example 173 using ethyl 4-amino-1-piperidinecarboxylate, dicyclohexylamine and 2-acetylamino-thiazole-5-sulfonylchloride.

HPLC-MS: m/z 556 (M+1).

Example 594 1-Cyclohex-3-enyl-1-cyclohexyl-3-thiazol-2-yl-urea

Cyclohex-3-enyl-cyclohexylamine was prepared by reductive amination ofcyclohex-3-enylamine and cyclohexanone using general procedure (B).Reaction with carbonyl diimidazole and 2-aminothiazole using generalprocedure (A) gave the title compound.

HPLC-MS: m/z 306 (M+1).

Example 5953-(5-Chloro-thiazol-2-yl)-1-cyclohex-3-enyl-1-cyclohexyl-urea

Cyclohex-3-enyl-cyclohexylamine was prepared by reductive amination ofcyclohex-3-enylamine and cyclohexanone using general procedure (B).Reaction with CDI and 5-chloro-2-aminothiazole using general procedure(A) gave the title compound.

HPLC-MS: m/z 341 (M+1).

Example 5961,1-Dicyclohexyl-3-(5-{2-[4-(4-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethylsulfanyl}-thiazol-2-yl)-urea

Prepared in a similar manner to Example 532 using1-(4-methoxyphenyl)piperazine

HPLC-MS: m/z 583 (M+1).

Example 5973-{5-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-1,1-dicyclohexyl-urea

Prepared in a similar manner to Example 532 using 1-acetylpiperazine

HPLC-MS: m/z 508 (M+1).

Example 5983-{5-[2-(4-Benzo[1,3]dioxol-5-yl-piperazin-1-yl)-2-oxo-ethylsulfanyl]-thiazol-2-yl}-1,1-dicyclohexyl-urea

Prepared in a similar manner to Example 532 using1-benzo[1,3]dioxol-5-yl-piperazine

HPLC-MS: m/z 586 (M+1).

Example 5991,1-Dicyclohexyl-3-(5-{2-[4-(1-methyl-piperidin-4-ylmethyl)-piperazin-1-yl]-2-oxo-ethylsulfanyl}-thiazol-2-yl)-urea

Prepared in a similar manner to Example 532 using1-(N-methyl-4-piperidinmethyl)piperazine

HPLC-MS: m/z 577 (M+1).

Example 6001,1-Dicyclohexyl-3-(5-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethylsulfanyl}-thiazol-2-yl)-urea

Prepared in a similar manner to Example 532 using1-(1-methyl-4-piperidinyl)piperazine.

HPLC-MS: m/z 563 (M+1).

Example 6013-(2-{3-(trans-4-Methyl-cyclohexyl)-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-ureido}-thiazol-5-ylsulfanyl)-propionicacid

3-(2-{3-(4-Methyl-cyclohexyl)-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-ureido}-thiazol-5-ylsulfanyl)-propionicacid ethyl ester was prepared in a similar manner to Example 554 using3-{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester and 4-morpholinecarbonyl chloride. Hydrolysis usinggeneral procedure (F) gave the title compound

HPLC-MS: m/z 541 (M+1).

Example 6023-{2-[3-(1-Dimethylsulfamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

3-{2-[3-(1-Dimethylsulfamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester was prepared in a similar manner to Example 554 using3-{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester and dimethylsulfamoyl chloride. Hydrolysis usinggeneral procedure (F) gave the title compound

HPLC-MS: m/z 535 (M+1).

Example 6033-{2-[3-(1-Dimethylcarbamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

3-{2-[3-(1-Dimethylcarbamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester was prepared in a similar manner to Example 554 using3-{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-propionicacid ethyl ester and dimethylcarbamoyl chloride. Hydrolysis usinggeneral procedure (F) gave the title compound

HPLC-MS: m/z 499 (M+1).

Example 6043-(5-Bromo-thiazol-2-yl)-1-[1-(2-fluoro-phenyl)-piperidin-4-yl]-1-(4-trans-methyl-cyclohexyl)-urea

The title compound was prepared (227 mg, 46%) in a manner similar togeneral procedure (C) using 5-bromo-2-aminothiazole (180 mg, 1.0 mmol),[1-(2-fluoro-phenyl)-piperidin-4-yl]-(4-trans-methyl-cyclohexyl)-amine(300 mg, 1.0 mmol), catalytic DMAP and CDI (163 mg, 1.0 mmol) indichloroethane.

¹H NMR (CDCl₃): δ 8.12 (br, 1H), 7. (s, 1H), 4 (s, 2H), 3. (m, 2H), 1.(m, 12H), 1. (m, 8H) ppm; HPLC-MS: m/z 497 (M+1).

Example 605 TTP-00214142{2-[3-[1-(2-Fluoro-phenyl)-piperidin-4-yl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester

The title compound was prepared (49 mg, 27%) as described in generalprocedure (D) using3-(5-bromo-thiazol-2-yl)-1-[1-(2-fluoro-phenyl)-piperidin-4-yl]-1-(4-trans-methyl-cyclohexyl)-urea(170 mg, 0.34 mmol), methyl thioglycolate (122 μL, 1.37 mmol) andpowdered K₂CO₃ (332 mg, 2.40 mmol) as the base.

¹H NMR (CDCl₃): δ 8.28 (br, 1H), 7.41 (s, 1H), 6.92-7.09 (m, 4H), 3.85(m, 1H), 3.72 (s, 3H), 3.52 (d, 2H), 3.40 (m, 3H), 2.75 (t, 2H), 2.25(m, 2H), 1.98 (m, 2H), 1.77 (m, 4H), 1.42 (m, 2H), 1.08 (m, 2H), 0.91(d, 3H) ppm; HPLC-MS: m/z 521 (M+1).

Example 606{2-[3-[1-(2-Fluoro-phenyl)-piperidin-4-yl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid

The title compound was prepared (17 mg, 58%) as described in generalprocedure (F) using{2-[3-[1-(2-fluoro-phenyl)-piperidin-4-yl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid methyl ester (30 mg, 0.057 mmol) and lithium hydroxide.

HPLC-MS: m/z 507 (M+1).

Example 6073-{2-[3-[1-(2-Fluoro-phenyl)-piperidin-4-yl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester

The title compound was prepared (42 mg, 36%) as described in generalprocedure (D) using3-(5-bromo-thiazol-2-yl)-1-[1-(2-fluoro-phenyl)-piperidin-4-yl]-1-(4-trans-methyl-cyclohexyl)-urea(107 mg, 0.22 mmol), methyl thiopropionate (72 μL, 0.65 mmol) andpowdered K₂CO₃ (180 mg, 1.29 mmol) as the base.

¹H NMR (CDCl₃): δ 8.33 (br, 1H), 7.35 (s, 1H), 6.91-7.11 (m, 4H), 3.88(m, 1H), 3.69 (s, 3H), 3.53 (d, 2H), 3.41 (m, 1H), 2.93 (t, 2H), 2.77(t, 2H), 2.62 (t, 2H), 2.26 (m, 2H), 2.00 (m, 2H), 1.60-1.88 (m, 5H),1.45 (m, 2H), 1.10 (m, 2H), 0.92 (d, 3H) ppm; HPLC-MS: m/z 535 (M+1).

Example 6083-{2-[3-[1-(2-Fluoro-phenyl)-piperidin-4-yl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid

The title compound was prepared (8 mg, 60%) as described in generalprocedure (F) using3-{2-[3-[1-(2-fluoro-phenyl)-piperidin-4-yl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionicacid methyl ester (15 mg, 0.028 mmol) and lithium hydroxide.

HPLC-MS: m/z 521 (M+1).

Pharmacological Methods

Glucokinase Activity Assay (I)

Glucokinase activity is assayed spectrometrically coupled to glucose6-phosphate dehydrogenase to determine compound activation ofglucokinase. The final assay contains 50 mM Hepes, pH 7.1, 50 mM KCl, 5mM MgCl₂, 2 mM dithiothreitol, 0.6 mM NADP, 1 mM ATP, 0.195 μM G-6-Pdehydrogenase (from Roche, 127 671), 15 nM recombinant humanglucokinase. The glucokinase is human liver glucokinase N-terminallytruncated with an N-terminal His-tag ((His)₈-VEQILA . . . Q466) and isexpressed in E. coli as a soluble protein with enzymatic activitycomparable to liver extracted GK.

The purification of His-tagged human glucokinase (hGK) was performed asfollows: The cell pellet from 50 ml E. coli culture was resuspended in 5ml extraction buffer A (25 mM HEPES, pH 8.0, 1 mM MgCl₂, 150 mM NaCl, 2mM mercaptoethanol) with addition of 0.25 mg/ml lysozyme and 50 μg/mlsodium azide. After 5 minutes at room temperature 5 ml of extractionbuffer B (1.5 M NaCl, 100 mM CaCl₂, 100 mM MgCl₂, 0.02 mg/ml DNase 1,protease inhibitor tablet (Complete® 1697498): 1 tablet pr. 20 mlbuffer) was added. The extract was then centrifugated at 15.000 g for 30minutes. The resulting supernatant was loaded on a 1 ml Metal ChelateAffinity Chromatography (MCAC) Column charged with Ni²⁺. The column iswashed with 2 volumes buffer A containing 20 mM imidazole and the boundhis-tagged hGK is subsequently eluted using a 20 minute gradient of 20to 500 mM imidazole in buffer A. Fractions are examined usingSDS-gel-electrophoresis, and fractions containing hGK (MW: 52 KDa) arepooled. Finally a gelfiltration step is used for final polishing andbuffer exchange. hGK containing fractions are loaded onto a Superdex 75(16/60) gelfiltration column and eluted with Buffer B (25 mM HEPES, pH8.0, 1 mM MgCl₂, 150 mM NaCl, 1 mM Dithiothreitol). The purified hGK isexamined by SDS-gel electrophoresis and MALDI mass spectrometry andfinally 20% glycerol is added before freezing. The yield from 50 ml E.coli culture is generally approximately 2-3 mg hGK with a purity>90%.

The compound to be tested is added into the well in final 2.5% DMSOconcentration in an amount sufficient to give a desired concentration ofcompound, for instance 1, 5, 10, 25 or 50 μM. The reaction starts afterglucose is added to a final concentration of 2, 5, 10 or 15 mM. Theassay uses a 96-well UV plate and the final assay volume used is 200μl/well. The plate is incubated at 25° C. for 5 min and kinetics ismeasured at 340 nm in SpectraMax every 30 seconds for 5 minutes. Resultsfor each compound are expressed as the fold activation of theglucokinase activity compared to the activation of the glucokinaseenzyme in an assay without compound after having been subtracted from a“blank”, which is without glucokinase enzyme and without compound. Thecompounds in each of the Examples exhibits activation of glucokinase inthis assay. A compound, which at a concentration of at or below 30 μMgives 1.5-fold higher glucokinase activity than the result from theassay without compound, is deemed to be an activator of glucokinase.

The glucose sensitivity of the compounds are measured at a compoundconcentration of 10 μM and at glucose concentrations of 5 and 15 mM.

Glucokinase Activity Assay (II)

Determination of Glycogen Deposition in Isolated Rat Hepatocytes:

Hepatocytes are isolated from rats fed ad libitum by a two-stepperfusion technique. Cell viability, assessed by trypan blue exclusion,is consistently greater than 80%. Cells are plated onto collagen-coated96-well plates in basal medium (Medium 199 (5.5 mM glucose) supplementedwith 0.1 μM dexamethasone, 100 units/ml penicillin, 100 mg/mlstreptomycin, 2 mM L-glutamine and 1 nM insulin) with 4% FCS at a celldensity of 30,000 cells/well. The medium is replaced with basal medium 1hour after initial plating in order to remove dead cells. Medium ischanged after 24 hours to basal medium supplemented with 9.5 mM glucoseand 10 nM insulin to induce glycogen synthesis, and experiments areperformed the next day. The hepatocytes are washed twice with prewarmed(37° C.) buffer A (117.6 mM NaCl, 5.4 mM KCl, 0.82 mM Mg₂SO₄, 1.5 mMKH₂PO₄, 20 mM HEPES, 9 mM NaHCO₃, 0.1% w/v HSA, and 2.25 mM CaCl₂, pH7.4 at 37° C.) and incubated in 100 μl buffer A containing 15 mM glucoseand increasing concentrations of the test compound, such as for instance1, 5, 10, 25, 50 or 100 μM, for 180 minutes. Glycogen content ismeasured using standard procedures (Agius, L. et al, Biochem J. 266,91-102 (1990). A compound, which when used in this assay gives ansignificant increase in glycogen content compared to the result from theassay without compound, is deemed to have activity in this assay.

Glucokinase Activity Assay (III)

Stimulation of Insulin Secretion by Glucokinase Activators in INS-1ECells

The glucose responsive β-cell line INS-1E is cultivated as described byAsfari M et al., Endocrinology, 130, 167-178 (1992). The cells are thenseeded into 96 well cell culture plates and grown to a density ofapproximately 5×10⁴ per well. Stimulation of glucose dependent insulinsecretion is tested by incubation for 2 hours in Krebs Ringer Hepesbuffer at glucose concentrations from 2.5 to 15 mM with or withoutaddition of glucokinase activating compounds in concentrations of forinstance 1, 5, 10, 25, 50 or 100 μM, and the supernatants collected formeasurements of insulin concentrations by ELISA (n=4). A compound, whichwhen used in this assay gives an significant increase in insulinsecretion in response to glucose compared to the result from the assaywithout compound, is deemed to have activity in this assay.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of the presentinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forglucokinase-deficiency mediated disease(s). Likewise, the specificpharmacological responses observed may vary according to and dependingon the particular active compound selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

1. A compound of formula (I)

wherein R¹ is

R² is

and R⁵ and R³¹ are independently selected from the group consisting ofhalogen, nitro, cyano, hydroxy, oxo, carboxy, —CF₃; or —NR¹⁰R¹¹; orC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy,aryl-C₁₋₆-alkoxy, heteroaryl, heteroaryl-C₁₋₆-alkoxy, aryloxy,heteroaryloxy, C₁₋₆-alkylthio, arylthio, heteroarylthio,C₃₋₈-cycloalkylthio, aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,C₁₋₆-alkylsulfenyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,C₁₋₆-alkylthio-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyloxy, amino-C₁₋₆-alkyl,C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,C₁₋₆-alkylsulfamoyl, di(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylsulfinamoyl ordi(C₁₋₆-alkyl)sulfinamoyl each of which is optionally substituted withone or more substituents independently selected from R¹²; or —C(O)—R²⁷,—S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —S(O)₂—NR¹³R¹⁴, —C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; R¹⁰and R¹¹ independently represent hydrogen, C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)OH,—S(O)₂—C₁₋₆-alkyl, or aryl; R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, aryl, aryl-C₁₋₆-alkyl, aryloxy-C₁₋₆-alkyl,aryl-C₂₋₆-alkenyl, heteroaryl, C₃₋₈-heterocyclyl, heteroaryl-C₁₋₆-alkyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, heteroaryloxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, carboxy-C₂₋₆-alkenyl, C₁₋₆-alkoxy-C₁₋₆-alkyl,C₁₋₆-alkoxy-C₂₋₆-alkenyl, C₁₋₆-alkylthio-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹—N—C₁₋₆-alkyl, R¹⁰R¹¹—N—C₂₋₆-alkenyl, R¹⁰R¹¹—N—S(O)₂—C₁₋₆-alkyl,R¹⁰R¹¹—N—C(O)—C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—NH—C₁₋₆-alkyl,aryl-C(O)—NH—C₁₋₆-alkyl, heteroaryl-C(O)—NH—C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C(O)—NH—C₁₋₆-alkyl, C₁₋₆-alkyl-S(O)₂—NH—C₁₋₆-alkyl,aryl-S(O)₂—NH—C₁₋₆-alkyl, heteroaryl-S(O)₂—NH—C₁₋₆-alkyl, orC₃₋₈-cycloalkyl-S(O)₂—NH—C₁₋₆-alkyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹²; R¹² is halogen, cyano, hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy, —CF₃,C₁₋₆-alkyl, C₁₋₆-alkoxy, —NR¹⁰R¹¹, —S(O)₂CH₃, or —S(O)₂NH₂; R¹³ and R¹⁴are independently selected from the group consisting of hydrogen,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, or heteroaryl,each of which is optionally substituted with one or more substituentsindependently selected from R¹⁵; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a 3 to 8 membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur; R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃, C₁₋₆-alkyl,—S(O)₂CH₃, or —S(O)₂NH₂; A is

R⁸ is selected from halogen, carboxy, cyano, nitro, hydroxy, —CF₃, —SCN;or C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,C₂₋₆-alkenylthio, C₁₋₆-alkylamino, C₁₋₆-alkylsulfenyl,—C(O)—O—C₁₋₆-alkyl, formyl, —C(O)—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl,—NH—C(O)—C₁₋₆-alkyl, —C₁₋₆-alkoxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-S—C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, or hydroxy-C₁₋₆-alkyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁶; or aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkylthio,heteroaryl-C₁₋₆-alkylthio, heteroaryl-thio-C₁₋₆-alkyl,heteroaryl-oxy-C₁₋₆-alkyl, aryloxy, heteroaryloxy, arylthio,heteroarylthio, aryl-C₁₋₆-alkylamino, —C(O)-aryl, or —C(O)-heteroaryl,each of which is optionally substituted on the aryl or heteroaryl partwith one or more substituents independently selected from R¹⁷; orC₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkylthio,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl,C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, each ofwhich is optionally substituted on the cycloalkyl part with one or moresubstituents independently selected from R¹⁸; or C₃₋₈-heterocyclyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkylthio,C₃₋₈-heterocyclylthio, C₃₋₈-heterocyclyl-amino-C₁₋₆-alkyl, or—C(O)—C₃₋₈-heterocyclyl, each of which is optionally substituted withone or more substituents independently selected from R¹⁶; or —NR¹⁹R²⁰,—C₁₋₆-alkyl-NR¹⁹R²⁰, —C₂₋₆-alkenyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹,—C₁₋₆-alkyl-S(O)—R²¹, —C₁₋₆-alkyl-S(O)₂—R²¹, —S(O)₂—R²¹ or—S(O)₂—NR¹⁹R²⁰, wherein each alkyl part may be substituted with one ormore substituents independently selected from R²⁵; or —C(O)NR²²R²³,—C₁₋₆-alkyl-C(O)NR²²R²³—C₁₋₆-alkyl-NH—NR²²R²³—C₁₋₆-alkyl-NH—C(O)—C₁₋₆-alkyl-NR²²R²³, each optionally substituted withone or more substituents independently selected from R²⁶; or R¹⁶, R¹⁷,and R¹⁸ are independently C₁₋₆-alkyl, halogen, nitro, cyano, hydroxy,carboxy, oxo, —CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—NR¹⁹R²⁰,—C(O)—O—C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl-C(O)—C₁₋₆-alkyl, —NR¹⁹R²⁰,—NHS(O)₂C₁₋₆-alkyl, —C(O)NR¹⁹R²⁰, —S(O)₂C₁₋₆-alkyl, or —S(O)₂NR¹⁹R²⁰;R¹⁹ and R²⁰ independently represent hydrogen, C₁₋₆-alkyl,hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, aryl, heteroaryl,C₃₋₈-heterocyclyl, aryl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³,or —S(O)₂—C₁₋₆-alkyl, each of which is optionally substituted with oneor more substituents independently selected from R²⁴, or R¹⁹ and R²⁰together with the nitrogen to which they are attached form a 3 to 8membered heterocyclic ring with the said nitrogen atom, the heterocyclicring optionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromR²⁴; R²¹ is selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, carboxy-C₁₋₆-alkyl,C₁₋₆-alkylamino-C₁₋₆-alkyl or hydroxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³;or aryl, heteroaryl, aryl-C₁₋₆-alkyl, or heteroaryl-C₁₋₆-alkyl, whereinthe aryl or heteroaryl part is optionally substituted with one or moresubstituents independently selected from R²⁴; or C₃₋₈-cycloalkyl,C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-cycloalkenyl-C₁₋₆-alkyl; R²² and R²³ are independently selectedfrom hydrogen, C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-S(O)₂—C₁₋₆-alkyl, C₃₋₈-cycloalkyl, aryl, or heteroaryl; orR²² and R²³ together with the nitrogen to which they are attached form a3 to 8 membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴; R²⁴ is halogen, nitro, cyano, hydroxy, carboxy, oxo,—CF₃, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C(O)—C₁₋₆-alkyl, —C(O)—C₃₋₈-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)—C₃₋₈-heterocyclyl-C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—C₃₋₈-heterocyclyl, —C(O)—O—C₁₋₆-alkyl-aryl,—NH—S(O)₂R²⁸, or —S(O)₂R²⁸, wherein each cyclic moiety is optionallysubstituted with one or more substituents independently selected fromR²⁹; R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, nitro, cyano,hydroxy, —C(O)—O—C₁₋₆-alkyl, carboxy, C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —CF₃, —S(O)₂CH₃, or —S(O)₂NH₂; R²⁸ is C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, C₃₋₈-cycloalkyl,aryl, aryl-C₁₋₆-alkyl, heteroaryl optionally substituted withC₁₋₆-alkyl, —NH₂, or —N(CH₃)₂; R²⁹ is halogen, nitro, cyano, hydroxy,carboxy, oxo, —CF₃, C₁₋₆-alkyl, or C₁₋₆-alkoxy; as well as any salthereof with a pharmaceutically acceptable acid or base, or any opticalisomer or mixture of optical isomers, racemic mixture, or tautomericform thereof.
 2. A compound according to claim 1, wherein R⁵ and R³¹ areindependently selected from the group consisting of halogen, oxo, cyano,hydroxy, carboxy, —CF₃; or —NR¹⁰R¹¹; or C₁₋₆-alkyl, C₂₋₆-alkenyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy,C₁₋₆-alkylthio, arylthio, —C(O)—O—C₁₋₆-alkyl, orC₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, each of which is optionally substitutedwith one or more substituents independently selected from R¹²; or—C(O)—R²⁷, —S(O)₂—R²⁷, —C(O)—NR¹³R¹⁴, —S(O)₂—NR¹³R¹⁴,—C₁₋₆-alkyl-C(O)—NR¹³R¹⁴; or two substituents selected from R³, R⁴, R⁵and R⁶ or R³⁰, R³¹, R³² and R³³ attached to the same or adjacent atomstogether form a radical —O—(CH₂)₁₋₃—O—.
 3. A compound according to claim2, wherein R⁵ and R³¹ are independently selected from the groupconsisting of halogen, oxo, —CF₃; or —NR¹⁰R¹¹; or C₁₋₆-alkyl,C₃₋₈-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryl, aryl-C₁₋₆-alkyl,arylthio, —C(O)—O—C₁₋₆-alkyl, or C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, each ofwhich is optionally substituted with one or more substituentsindependently selected from R¹²; or —C(O)—R²⁷, —S(O)₂—NR¹³R¹⁴ or—S(O)₂—R²⁷; or two substituents selected from R³, R⁴, R⁵ and R⁶ or R³⁰,R³¹, R³² and R³³ attached to the same or adjacent atoms together form aradical —O—(CH₂)₁₋₃—O—.
 4. A compound according to claim 3, wherein R⁵and R³¹ are independently selected from the group consisting of halogen,—CF₃; or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphtyl,benzyl, phenyl-ethyl, methoxy, ethoxy, propoxy, phenylthio, —C(O)—O—CH₃,or —C(O)—O—CH₂CH₃, each of which is optionally substituted with one ormore substituents independently selected from R¹²; or —C(O)—R²⁷,—S(O)₂—NR¹³R¹⁴ or —S(O)₂—R²⁷; or two substituents selected from R³, R⁴,R⁵ and R⁶ or R³⁰, R³¹, R³² and R³³ attached to the same or adjacentatoms together form a radical —O—(CH₂)₁₋₃—O—.
 5. A compound according toclaim 4, wherein R⁵ and R³¹ are independently selected from the groupconsisting of halogen, —CF₃; or methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy, propoxy, phenylthio,—C(O)—O—CH₃, or —C(O)—O—CH₂CH₃, each of which is optionally substitutedwith one or more substituents independently selected from R¹²; or—C(O)—R²⁷, —S(O)₂—NR¹³R¹⁴ or —S(O)₂—R²⁷.
 6. A compound according toclaim 5, wherein R⁵ and R³¹ are independently selected from the groupconsisting of F, Cl, —CF₃, methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, methoxy, ethoxy, propoxy, —C(O)—R²⁷, —S(O)₂—NR¹³R¹⁴ or—S(O)₂—R²⁷.
 7. A compound according to claim 3, wherein R⁵ and R³¹ areindependently selected from C₁₋₆-alkyl, C₁₋₆-alkoxy, —S(O)₂—R²⁷ or—C(O)—R²⁷.
 8. A compound according to claim 1, wherein R¹⁰ and R¹¹independently represent hydrogen, methyl, ethyl, propyl, —C(O)—CH₃,—C(O)—CH₂CH₃, —CH₂C(O)OH, —CH₂CH₂C(O)OH, —C(O)—CH₂—C(O)OH,—C(O)—CH₂CH₂—C(O)OH, —S(O)₂CH₃, or phenyl.
 9. A compound according toclaim 8, wherein R¹⁰ and R¹¹ independently represent hydrogen, methyl,ethyl, —C(O)—CH₃, —CH₂C(O)OH, —C(O)—CH₂—C(O)OH, —S(O)₂CH₃, or phenyl.10. A compound according to claim 9, wherein R¹⁰ and R¹¹ independentlyrepresent hydrogen, methyl, ethyl, or phenyl.
 11. A compound accordingto claim 1, wherein R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, heteroaryl, heteroaryl-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkylthio-C₁₋₆-alkyl,R¹⁰HN—C₁₋₆-alkyl, R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N—S(O)₂—C₁₋₆-alkyl, orR¹⁰R¹¹N—C(O)—C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹².
 12. A compoundaccording to claim 11, wherein R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl, aryl,heteroaryl, heteroaryl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl, R¹⁰HN—C₁₋₆-alkyl,R¹⁰R¹¹N—C₁₋₆-alkyl, R¹⁰R¹¹N(O)₂—C₁₋₆-alkyl, or R¹⁰R¹¹N(O)—C₁₋₆-alkyl,each of which is optionally substituted with one or more substituentsindependently selected from R¹².
 13. A compound according to claim 12,wherein R²⁷ is C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, heteroaryl-C₁₋₆-alkyl,aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, orheteroaryl, each of which is optionally substituted with one or moresubstituents independently selected from R¹².
 14. A compound accordingto claim 13, wherein R²⁷ is methyl, ethyl, propyl, n-butyl, isobutyl,1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl,phenyl, pyridyl, thiophene, imidazole, or thiazole, each of which isoptionally substituted with one or more substituents independentlyselected from R¹².
 15. A compound according to claim 14, wherein R²⁷ ismethyl, ethyl, propyl, n-butyl, isobutyl, 1,1,1-trifluoroethyl,cyclopropyl, cyclopentyl, cyclopropylmethyl, phenyl, or pyridyl,thiophene, imidazole, or thiazole.
 16. A compound according to claim 1,wherein R¹² is halogen, cyano, hydroxy, carboxy, —CF₃, or C₁₋₆-alkyl.17. A compound according to claim 16, wherein R¹² is halogen, cyano,hydroxy, carboxy, —CF₃, methoxy, methyl, ethyl or propyl.
 18. A compoundaccording to claim 17, wherein R¹² is halogen, carboxy, methyl, ethyl orpropyl.
 19. A compound according to claim 1, wherein R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, or naphtyl,each of which is optionally substituted with one or more substituentsindependently selected from R¹⁵; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a 3- to 8-membered heterocyclicring with the said nitrogen atom, the heterocyclic ring optionallycontaining one or two further heteroatoms selected from nitrogen, oxygenand sulphur.
 20. A compound according to claim 19, wherein R¹³ and R¹⁴are independently selected from the group consisting of hydrogen,methyl, ethyl, propyl, hydroxy-methyl, hydroxy-ethyl, carboxy-methyl,carboxy-ethyl, phenyl, or naphtyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁵; or R¹³ and R¹⁴ together with the nitrogen to which they areattached form a 3- to 8-membered heterocyclic ring with the saidnitrogen atom, the heterocyclic ring optionally containing one or twofurther heteroatoms selected from nitrogen, oxygen and sulphur.
 21. Acompound according to claim 20, wherein R¹³ and R¹⁴ are independentlyselected from the group consisting of hydrogen, methyl, ethyl, propyl,or phenyl, each of which is optionally substituted with one or moresubstituents independently selected from R¹⁵.
 22. A compound accordingto claim 1, wherein R¹⁵ is halogen, cyano, hydroxy, carboxy, —CF₃,methyl, ethyl, or propyl.
 23. A compound according to claim 22, whereinR¹⁵ is halogen, hydroxy, carboxy, —CF₃, methyl, or ethyl.
 24. A compoundaccording to claim 1, wherein R⁸ is selected from halogen, carboxy,cyano, nitro, hydroxy, —CF₃, —SCN; or C₁₋₆-alkyl, C₂₋₆-alkenyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-alkylsulfenyl,—C(O)—O—C₁₋₆-alkyl, —NH—C(O)—C₁₋₆-alkyl, —C₁₋₆-alkoxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-S—C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio each ofwhich is optionally substituted with one or more substituentsindependently selected from R¹⁶; or aryl, heteroaryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, aryl-C₁₋₆-alkoxy, heteroaryl-C₁₋₆-alkoxy,heteroaryl-thio-C₁₋₆-alkyl, aryloxy, heteroaryloxy, heteroarylthio, eachof which is optionally substituted on the aryl or heteroaryl part withone or more substituents independently selected from R¹⁷; orC₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₃₋₈-cycloalkenyl-C₁₋₆-alkyl, eachof which is optionally substituted on the cycloalkyl part with one ormore substituents independently selected from R¹⁸; or C₃₋₈-heterocyclyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, C₃₋₈-heterocyclylthio, or—C(O)—C₃₋₈-heterocyclyl, each of which is optionally substituted withone or more substituents independently selected from R¹⁶; or —NR¹⁹R²⁰,—C₁₋₆-alkyl-NR¹⁹R²⁰, —C₁₋₆-alkyl-S—R²¹, —C₁₋₆-alkyl-S(O)—R²¹,—C₁₋₆-alkyl-S(O)₂—R²¹, S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰, wherein each alkylpart may be substituted with one or more substituents independentlyselected from R²⁵; or —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionallysubstituted with one or more substituents independently selected fromR²⁶.
 25. A compound according to claim 24, wherein R⁸ is selected fromhalogen, carboxy, cyano, or —CF₃; or C₁₋₆-alkyl, C₂₋₆-alkenyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, —C(O)—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkoxy-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of which is optionally substituted withone or more substituents independently selected from R¹⁶; or aryl,heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl, each of which isoptionally substituted on the aryl or heteroaryl part with one or moresubstituents independently selected from R¹⁷; or C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, each of which is optionally substituted onthe cycloalkyl part with one or more substituents independently selectedfrom R¹⁸; or C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or—C(O)—C₃₋₈-heterocyclyl, each of which is optionally substituted withone or more substituents independently selected from R¹⁶; or NR¹⁹R²⁰,—C₁₋₆-alkyl-NR¹⁹R²⁰, —S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰, wherein each alkylpart may be substituted with one or more substituents independentlyselected from R²⁵; or —C(O)NR²²R²³, —C₁₋₆-alkyl-C(O)NR²²R²³ optionallysubstituted with one or more substituents independently selected fromR²⁶.
 26. A compound according to claim 25, wherein R⁸ is selected fromhalogen, carboxy or —CF₃; or C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-O—C(O)—C₁₋₆-alkyl or—C(O)—O—C₁₋₆-alkyl, each of which is optionally substituted with one ormore substituents independently selected from R¹⁶; or phenyl, benzyl, orheteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, and whereineach aryl or heteroaryl is optionally substituted on the aryl orheteroaryl part with one or more substituents independently selectedfrom R¹⁷; or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachof which is optionally substituted on the cycloalkyl part with one ormore substituents independently selected from R¹⁸; or pyrrolidinyl,piperidyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁶; or —C(O)NR²²R²³, —S(O)₂—R²¹ or —S(O)₂—NR¹⁹R²⁰.
 27. A compoundaccording to claim 26, wherein R⁸ is selected from halogen, carboxy,—CF₃, —S—CH₃, —S—CH₂CH₃, —S—CH₂CH₂CH₃, methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —CH₂—O—C(O)—CH₃,—CH₂—O—C(O)—CH₂CH₃, —CH₂CH₂—O—C(O)—CH₃, —CH₂CH₂—O—C(O)—CH₂CH₃,—C(O)—O—CH₃, —C(O)—O—CH₂CH₃, each of which is optionally substitutedwith one or more substituents independently selected from R¹⁶; orheteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, eachoptionally substituted on the heteroaryl part with one or moresubstituents independently selected from R¹⁷, or pyrrolidinyl,piperidyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with one or more substituents independently selected fromR¹⁶, or —S(O)₂—R²¹.
 28. A compound according to claim 27, wherein R⁸ isselected from Cl, F, Br, —CF₃, —S—CH₃, —S—CH₂CH₃, —S—CH₂CH₂CH₃, methyl,ethyl, methoxy, ethoxy, —CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, or—C(O)—O—CH₂CH₃, each of which is optionally substituted with one or moresubstituents independently selected from R¹⁶; or heteroarylthio, whereinheteroaryl is pyridyl or imidazolyl, each optionally substituted on theheteroaryl part with one or more substituents independently selectedfrom R¹⁷, or pyrrolidinyl, piperidyl, piperazinyl, or morpholinyl, eachof which is optionally substituted with one or more substituentsindependently selected from R¹⁶.
 29. A compound according to claim 1,wherein R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, halogen,hydroxy, oxo, carboxy, —CF₃, carboxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, —NR¹⁹R²⁰,—C(O)NR¹⁹R²⁰ or —S(O)₂—C₁₋₆-alkyl.
 30. A compound according to claim 29,wherein R¹⁶, R¹⁷, and R¹⁸ are independently methyl, ethyl, propyl,halogen, hydroxy, oxo, carboxy, —CF₃, carboxy-methyl, carboxy-ethyl,carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl,—CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂—C(O)—O—CH₃,—CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃, —C(O)—O—CH₂CH₂CH₃,or —S(O)₂CH₃.
 31. A compound according to claim 30, wherein R¹⁶, R¹⁷,and R¹⁸ are independently methyl, ethyl, propyl, halogen, oxo, carboxy,carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl,hydroxy-ethyl, hydroxy-propyl, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—O—CH₂CH₃,—CH₂CH₂—C(O)—O—CH₃, —CH₂CH₂—C(O)—O—CH₂CH₃, —C(O)—O—CH₃, —C(O)—O—CH₂CH₃,—C(O)—O—CH₂CH₂CH₃, or —S(O)₂CH₃.
 32. A compound according to claim 29,wherein R¹⁶, R¹⁷, and R¹⁸ are independently C₁₋₆-alkyl, carboxy,—NR¹⁹R²⁰, —C(O)—O—C₁₋₆-alkyl or —C(O)NR¹⁹R²⁰.
 33. A compound accordingto claim 1, wherein R¹⁹ and R²⁰ independently represent hydrogen,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, phenyl, naphtyl,C₃₋₈-heterocyclyl, phenyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³or —S(O)₂—C₁₋₆-alkyl, each of which is optionally substituted with oneor more substituents independently selected from R²⁴; or R¹⁹ and R²⁰together with the nitrogen to which they are attached form a 3- to8-membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴.
 34. A compound according to claim 33, wherein R¹⁹ andR²⁰ independently represent hydrogen, methyl, ethyl, propyl,carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl,hydroxy-ethyl, hydroxy-propyl, phenyl, phenyl-C₁₋₆-alkyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³, or naphtyl, or R¹⁹and R²⁰ together with the nitrogen to which they are attached form a 3-to 8-membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴.
 35. A compound according to claim 33, wherein R¹⁹ andR²⁰ independently represent hydrogen, C₁₋₆-alkyl, or R¹⁹ and R²⁰together with the nitrogen to which they are attached form a 3- to8-membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴.
 36. A compound according to claim 35, wherein R¹⁹ andR²⁰ independently represent hydrogen, methyl, ethyl, or propyl, or R¹⁹and R²⁰ together with the nitrogen to which they are attached form a 3-to 8-membered heterocyclic ring with the said nitrogen atom, wherein theheterocyclic ring is pyrrolidyl, piperidyl, piperazinyl,homopiperazinyl, or morpholinyl, the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromR²⁴.
 37. A compound according to claim 1, wherein R²¹ is selected fromC₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-NR²²R²³ orhydroxy-C₁₋₆-alkyl; or phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, whereinthe aryl part is optionally substituted with one or more substituentsindependently selected from R²⁴; or C₃₋₈-cycloalkyl, orC₃₋₈-cycloalkyl-C₁₋₆-alkyl.
 38. A compound according to claim 37,wherein R²¹ is selected from methyl, ethyl, propyl, carboxy-methyl,carboxy-ethyl, carboxy-propyl, hydroxy-methyl, hydroxy-ethyl,hydroxy-propyl; or phenyl, naphtyl, or phenyl-C₁₋₆-alkyl, wherein thearyl part is optionally substituted with one or more substituentsindependently selected from R²⁴; or C₃₋₈-cycloalkyl, orC₃₋₈-cycloalkyl-C₁₋₆-alkyl.
 39. A compound according to claim 38,wherein R²¹ is selected from methyl, ethyl, carboxy-methyl,carboxy-ethyl, carboxy-propyl; or phenyl, naphtyl, or phenyl-C₁₋₆-alkyl,wherein the aryl part is optionally substituted with one or moresubstituents independently selected from R²⁴.
 40. A compound accordingto claim 1, wherein R²² and R²³ are independently selected fromhydrogen, C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,—C(O)—O—C₁₋₆-alkyl, C₃₋₈-cycloalkyl, phenyl, naphtyl, or R²² and R²³together with the nitrogen to which they are attached form a 3- to8-membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from R²⁴.
 41. A compound according to claim 40, wherein R²² andR²³ are independently selected from hydrogen, methyl, ethyl, propyl,butyl, carboxymethyl, carboxyethyl, carboxypropyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphtyl, orR²² and R²³ together with the nitrogen to which they are attached form a3- to 8-membered heterocyclic ring with the said nitrogen atom, whereinthe heterocyclic ring is pyrrolidyl, piperidyl, piperazinyl,homopiperazinyl, or morpholinyl, the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromR²⁴.
 42. A compound according to claim 41, wherein R²² and R²³ togetherwith the nitrogen to which they are attached form a 3- to 8-memberedheterocyclic ring with the said nitrogen atom, wherein the heterocyclicring is pyrrolidyl, piperidyl, piperazinyl, homopiperazinyl, ormorpholinyl, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from R²⁴.
 43. A compoundaccording to claim 1, wherein R²⁴ is halogen, hydroxy, carboxy, oxo,—CF₃, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl,aryl, heteroaryl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl-aryl, or —S(O)₂R²⁸,wherein aryl is phenyl or naphtyl, and heteroaryl is pyridyl orpyrimidyl, and wherein each cyclic moiety is optionally substituted withone or more substituents independently selected from R²⁹.
 44. A compoundaccording to claim 43, wherein R²⁴ is halogen, hydroxy, carboxy, oxo,—CF₃, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl,—C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl,heteroaryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or —S(O)₂R²⁸,wherein aryl is phenyl or naphtyl, and heteroaryl is pyridyl orpyrimidyl, and wherein each cyclic moiety is optionally substituted withone or more substituents independently selected from R²⁹.
 45. A compoundaccording to claim 44, wherein R²⁴ is halogen, carboxy, oxo, —CF₃,C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, —C(O)—C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl,aryl, aryl-C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or —S(O)₂R²⁸, wherein aryl is phenyl ornaphtyl, and wherein each cyclic moiety is optionally substituted withone or more substituents independently selected from R²⁹.
 46. A compoundaccording to claim 45, wherein R²⁴ is carboxy, oxo, C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, —C(O)—O—C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl,C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, C₃₋₈-heterocyclyl-C₁₋₆-alkyl, or—S(O)₂R²⁸, wherein aryl is phenyl or naphtyl, and wherein each cyclicmoiety is optionally substituted with one or more substituentsindependently selected from R²⁹.
 47. A compound according to claim 1,wherein R²⁵ and R²⁶ are independently C₁₋₆-alkyl, halogen, hydroxy,carboxy, or —CF₃.
 48. A compound according to claim 47, wherein R²⁵ andR²⁶ are independently methyl, ethyl, propyl, halogen, hydroxy, carboxy,or —CF₃.
 49. A compound according to claim 1, wherein R²⁸ is C₁₋₆-alkyl,—C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, phenyl, phenyl-C₁₋₆-alkyl, heteroaryloptionally substituted with C₁₋₆-alkyl or —N(CH₃)₂, wherein heteroarylis imidazolyl, pyridyl or pyrimidyl.
 50. A compound according to claim49, wherein R²⁸ is C₁₋₆-alkyl, —C₁₋₆-alkyl-C(O)—O—C₁₋₆-alkyl, or—N(CH₃)₂.
 51. A compound according to claim 1, wherein R²⁹ is halogen,carboxy, —CF₃, C₁₋₆-alkyl, or C₁₋₆-alkoxy.